Pyrazole compound and pharmaceutical use thereof

ABSTRACT

A compound of the following general Formula [Ib]: 
     
       
         
         
             
             
         
       
     
     wherein each symbol is the same as defined in the description; or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 14/445,500,filed Jul. 29, 2014, which is incorporated herein by reference in itsentirety and which is a continuation of application Ser. No. 13/599,665,filed Aug. 30, 2012, now issued as U.S. Pat. No. 8,846,746, which claimsthe benefit of Provisional Application No. 61/573,433, filed Sep. 6,2011, and the priority benefit of Japanese Patent Application No.2011-188121, filed Aug. 31, 2011.

TECHNICAL FIELD

The present invention relates to a pyrazole compound having SGLT1inhibitory activity or a pharmaceutically acceptable salt thereof, apharmaceutical composition comprising the same, and its pharmaceuticaluse.

BACKGROUND ART

It is known that SGLT1 (i.e., Sodium-Glucose Co-transporter 1)contributes to a great portion of absorption of glucose and galactose inthe small intestine. It is reported that human SGLT1-deficiency inpatients causes glucose-galactose malabsorption. Furthermore, it isconfirmed that the expression of SGLT1 in the small intestine increasesin diabetic patients and it is thought that increased sugar absorptionin diabetic patients is caused by the high expression of SGLT1 in thesmall intestine.

From these knowledge, a SGLT1 inhibitor is expected to normalize theblood glucose level, since it blocks glucose absorption in the smallintestine. Therefore, a SGLT1 inhibitor is considered to be effectiveagainst diabetes and diabetic complications associated withhyperglycemia, specifically retinopathy, nephropathy and neuropathywhich are known as microangiopathy, and cerebrovascular disease,ischemic heart disease and membrum-inferius arteriosclerosis obliteranswhich are known as macroangiopathy. Moreover, it is thought to beeffective against obesity by inhibiting the inflow of glucose into thebody (non-patent literatures 1 and 2).

In addition, SGLT1 is expressed in cardiac muscle cells. It is knownthat GLUT1 and GLUT4 (Glucose Transporter Type 4) usually have a role inuptake of glucose to cardiac muscle cells and the contribution of SGLT1is small. However, the expression of SGLT1 is induced in the cardiacmuscles of mice into which was introduced mutated genes of PRKAG2 (gamma2 subunit of AMPK (AMP-Activated Protein Kinase)) which is a responsiblegene of familial hypertrophic cardiomyopathy (glycogen accumulation-typemyocardosis), or mice which underwent myocardial ischemia treatment, andSGLT1 is reported to have contributed to the uptake of glucose tocardiac muscle cells in these pathologies. Glucose incorporated by SGLT1is thought to be excessively accumulated or metabolized within cardiacmuscle cells and impaire the cells. It is reported in the former mousemodel that accumulation of glycogen in the cardiac muscle is actuallyinhibited by the treatment of phlorizin which is a non-selective SGLTinhibitor.

From these knowledge, a SGLT1 inhibitor is thought to be effectiveagainst hypertrophic cardiomyopathy and ischemic heart disease byinhibiting uptake of excess glucose into cardiac muscle cells(non-patent literatures 3 and 4).

SGLT1 is stabilized by epidermal growth factor receptors (i.e., surfaceproteins on many kinds of cancer cells) in cancer cells. It is knownthat transporters of glucose, lactic acid, and amino acid, etc. areinvolved in nutrition supply to cancer cells, and especially, regardingthe transportation of glucose, SGLT1 and GLUT1 supply glucose to cancercells, continuously. When glucose is not supplied over a long period oftime, cells are destroyed by autophagy.

From these knowledge, a SGLT1 inhibitor is thought to inhibit supply ofglucose to cancer cells and show anticancer activity (non-patentliteratures 5 and 6).

Since carbohydrate in diet is degraded to monosaccharide in thegastrointestinal tracts and is absorbed in the upper gastrointestinaltracts, not so many sugar would reach the lower gastrointestinal tracts.However, when drugs which delay and/or inhibit glucose absorption areadministered, or a large amount of resistant polysaccharide areingested, undigested sugar would be retained in the lowergastrointestinal tracts and the undigested sugar retained in the lowergastrointestinal tracts would cause osmotic diarrhea.

The amount of monosaccharide in the lower gastrointestinal tracts isincreased by the inhibition of glucose absorption by a SGLT1 inhibitor.Therefore, it is believed that a SGLT1 inhibitor is effective againstconstipation.

Non-Patent Document

-   [Non-patent literature 1] Am J Physiol Gastrointest Liver Physiol.    2002; 282(2):G241-8-   [Non-patent literature 2] Nature. 1991; 350(6316): 354-6-   [Non-patent literature 3] J Mol Cell Cardiol. 2010; 49(4):683-92-   [Non-patent literature 4] Cardiovasc Res. 2009; 84(1):111-8-   [Non-patent literature 5] Cancer Cell. 2008, 13: 385-93-   [Non-patent literature 6] Pharmacol Ther. 2009, 121: 29-40

SUMMARY OF INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a pyrazole compounduseful as a medicine which has SGLT1 inhibitory activity, or apharmaceutically acceptable salt thereof, and a pharmaceuticalcomposition comprising the same.

Means to Solve the Problems

The present invention is as follows.

Paragraph 1: A compound or a pharmaceutically acceptable salt thereofrepresented by the following general formula [I]:

Wherein

Ring Cy is

(1) C₆₋₁₀ aryl,(2) C₃₋₈ cycloalkyl or(3) C₃₋₈ cycloalkenyl,n1 is 0, 1, 2, 3 or 4,

R¹ is

(1) a halogen atom,(2) hydroxy,(3) carboxy,(4) a C₁₋₆ alkyl group,(5) a C₁₋₆ alkoxy group,(6) a C₃₋₆ cycloalkyl group,(7) a halo C₁₋₆ alkyl group,(8) a hydroxy C₁₋₆ alkyl group,(9) a C₁₋₆ alkoxy C₁₋₆ alkyl group,(10) a halo C₁₋₆ alkoxy group or(11) a carboxy C₁₋₆ alkoxy group,provided when n1 is 2, 3 or 4, R¹ each is the same or different,

R² is

(1) a C₁₋₈ alkyl group,(2) a C₃₋₈ cycloalkyl C₁₋₆ alkyl group,(3) a C₆₋₁₀ aryl C₁₋₆ alkyl group,(4) a saturated heterocyclo C₁₋₆ alkyl group (the saturated heterocycleis of 5-membered to 6-membered saturated heterocycle having 1 to 2heteroatoms selected from nitrogen, oxygen, and sulfur),(5) a C₃₋₈ cycloalkyl group,(6) a halo C₁₋₆ alkyl group,(7) a C₁₋₆ alkoxy C₁₋₆ alkyl group,(8) a halo C₃₋₈ cycloalkyl group,(9) a C₆₋₁₀ aryl group (the C₆₋₁₀ aryl group is optionally substitutedby 1 to 4 substituents selected from

-   -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group,    -   (c) a C₁₋₆ alkoxy group and    -   (d) a carboxy C₁₋₆ alkoxy group), or        (10) a saturated heterocycle group (the saturated heterocycle is        of 5-membered to 6-membered saturated heterocycle having 1 to 2        heteroatoms selected from nitrogen, oxygen, and sulfur, and is        optionally substituted by 1 to 4 C₁₋₆ alkyl groups),        n2 is 0, 1, 2, 3 or 4,        m is 0, 1, 2, 3 or 4,

R³ is

(1) a C₁₋₆ alkyl group or(2) a hydroxy C₁₋₆ alkyl group,provided when n2 is 2, 3 or 4, R³ each is the same or different,

X^(a) is

(1) a bond or(2) N—R⁴ (the R⁴ is

-   -   (a) a hydrogen atom or    -   (b) a C₁₋₆ alkyl group), and

X^(b) is

-   -   (1) NH or    -   (2) an oxygen atom,    -   provided, when X^(a) is N—R⁴, X^(b) is not an oxygen atom.

Paragraph 2: The compound or a pharmaceutically acceptable salt thereofaccording to paragraph 1, wherein X^(b) is NH.

Paragraph 3: The compound or a pharmaceutically acceptable salt thereofaccording to paragraph 1 or 2, wherein the ring Cy is C₆₋₁₀ aryl.

Paragraph 4: The compound or a pharmaceutically acceptable salt thereofaccording to paragraph 3, wherein the ring Cy is phenyl.

Paragraph 5: The compound or a pharmaceutically acceptable salt thereofaccording to any one of paragraphs 1 to 4, wherein R¹ is

(1) a halogen atom,(2) a C₁₋₆ alkyl group,(3) a C₁₋₆ alkoxy group,(4) a halo C₁₋₆ alkyl group,(5) a C₁₋₆ alkoxy C₁₋₆ alkyl group or(6) a halo C₁₋₆ alkoxy group,provided when n1 is 2, 3 or 4, R¹ each is the same or different.

Paragraph 6: The compound or a pharmaceutically acceptable salt thereofaccording to any one of paragraphs 1 to 5,

wherein R² is a C₆₋₁₀ aryl group (the C₆₋₁₀ aryl group is optionallysubstituted by 1 to 4 substituents selected from(a) a halogen atom,(b) a C₁₋₆ alkyl group,(c) a C₁₋₆ alkoxy group and(d) a carboxy C₁₋₆ alkoxy group).

Paragraph 7: The compound or a pharmaceutically acceptable salt thereofaccording to paragraph 6, wherein R² is a phenyl group (the phenyl groupk is optionally substituted by 1 to 4 substituents selected from

(a) a halogen atom,(b) a C₁₋₆ alkyl group,(c) a C₁₋₆ alkoxy group and(d) a carboxy C₁₋₆ alkoxy group).

Paragraph 8: A pharmaceutical composition which comprises a compound ora pharmaceutically acceptable salt thereof according to any one ofparagraphs 1 to 7, and a pharmaceutically acceptable carrier.

Paragraph 9: A SGLT1 inhibitor which comprises a compound or apharmaceutically acceptable salt thereof according to any one ofparagraphs 1 to 7

Paragraph 10: An agent for treating or preventing diabetes whichcomprises a compound or a pharmaceutically acceptable salt thereofaccording to any one of paragraphs 1 to 7.

Paragraph 11: The agent for treating or preventing diabetes according toparagraph 10, wherein diabetes is type II diabetes mellitus.

Paragraph 12: A method for inhibiting of SGLT1 which comprisesadministrating to mammals a therapeutically effective amount of acompound dr a pharmaceutically acceptable salt thereof according to anyone of paragraphs 1 to 7

Paragraph 13: A method for treating or preventing diabetes whichcomprises administrating to mammals a therapeutically effective amountof a compound or a pharmaceutically acceptable salt thereof according toany one of paragraphs 1 to 7.

Paragraph 14: The method according to paragraph 13, wherein the diabetesis type II diabetes mellitus.

Paragraph 15: Use of a compound or a pharmaceutically acceptable saltthereof according to any one of paragraphs 1 to 7 for manufacturing aSGLT1 inhibitor.

Paragraph 16: The use of a compound or a pharmaceutically acceptablesalt thereof according to any one of paragraphs 1 to 7, formanufacturing an agent fot treating or preventing diabetes.

Paragraph 17: The use according to paragraph 16, wherein the diabetes istype II diabetes mellitus.

Paragraph 18: A kit for commerce comprising

(a) a pharmaceutical composition which comprises a compound or apharmaceutically acceptable salt thereof according to any one ofparagraphs 1 to 7 as an active ingredient, and(b) a package insert about the pharmaceutical composition whichindicates that the pharmaceutical composition can be used or should beused for treatment or prevention of type II diabetes mellitus.

Paragraph 19: A package for commerce comprising

(a) a pharmaceutical composition which comprises a compound or apharmaceutically acceptable salt thereof according to any one ofparagraphs 1 to 7 as an active ingredient, and(b) a package insert about the pharmaceutical composition whichindicates that the pharmaceutical composition can be used or should beused for treatment or prevention of type II diabetes mellitus.

Paragraph 20: A compound or a pharmaceutically acceptable salt thereofrepresented by the general formula [Ib]:

wherein

Ring Cy is

(1) C₆₋₁₀ aryl,(2) C₃₋₈ cycloalkyl or(3) C₃₋₈ cycloalkenyl,n1 is 0, 1, 2, 3 or 4,

R^(1a) is

(1) a halogen atom,(2) hydroxy,(3) carboxy,(4) a C₁₋₆ alkyl group,(5) a C₂₋₈ alkenyl group,(6) a C₂₋₈ alkynyl group,(7) a C₁₋₆ alkoxy group,(8) a C₃₋₆ cycloalkyl group,(9) a halo C₁₋₆ alkyl group,(10) a hydroxy C₁₋₆ alkyl group,(11) a C₁₋₆ alkoxy C₁₋₆ alkyl group,(12) a halo C₁₋₆ alkoxy C₁₋₆ alkyl group,(13) a C₁₋₆ alkylsulfonyl C₁₋₆ alkyl group,(14) a halo C₁₋₆ alkylsulfonyl C₁₋₆ alkyl group,(15) a halo C₁₋₆ alkylamino C₁₋₆ alkyl group,(16) a C₃₋₆ cycloalkyl C₂₋₆ alkynyl group(17) a halo C₁₋₆ alkoxy group,(18) a carboxy C₁₋₆ alkoxy group,(19) a C₁₋₆ alkylsulfanyl group,(20) a C₁₋₆ alkylsulfonyl group,(21) a halo C₁₋₆ alkylsulfonyl group,(22) a C₁₋₈ alkylcarbonyl group,(23) a C₁₋₆ alkyloxycarbonyl group,(24) a group represented by the Formula:

wherein

R₅ is

-   -   (a) a hydrogen atom or    -   (b) a C₁₋₆ alkyl group, and

R₆ is

-   -   (a) a C₁₋₆ alkyl group or    -   (b) a halo C₁₋₆ alkyl group,

(25) a saturated heterocyclo C₁₋₆ alkyl group (the saturated heterocycleis of 4-membered to 6-membered saturated heterocycle having 1 to 2heteroatoms selected from nitrogen, oxygen, and sulfur) or

(26) a saturated heterocyclo oxy C₁₋₆ alkyl group (the saturatedheterocycle is of 4-membered to 6-membered saturated heterocycle having1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur), providedwhen n1 is 2, 3 or 4, R^(1a) each is the same or different,

R^(2a) is

(1) a C₁₋₈ alkyl group,(2) a C₃₋₈ cycloalkyl C₁₋₆ alkyl group,(3) a C₆₋₁₀ aryl C₁₋₆ alkyl group,(4) a saturated heterocyclo C₁₋₆ alkyl group (the saturated heterocycleis of 4-membered to 6-membered saturated heterocycle having 1 to 2heteroatoms selected from nitrogen, oxygen, and sulfur),(5) a C₃₋₈ cycloalkyl group,(6) a halo C₁₋₆ alkyl group,(7) a C₁₋₆ alkoxy C₁₋₆ alkyl group,(8) a halo C₃₋₈ cycloalkyl group,(9) a C₆₋₁₀ aryl group (the C₆₋₁₀ aryl group is optionally substitutedby 1 to 4 substituents selected from

-   -   (a) a halogen atom,    -   (b) hydroxy,    -   (c) a C₁₋₆ alkyl group,    -   (d) a C₂₋₈ alkenyl group,    -   (e) a C₂₋₆ alkynyl group,    -   (f) a C₁₋₆ alkoxy group,    -   (g) a halo C₁₋₆ alkyl group,    -   (h) a C₁₋₆ alkoxy C₁₋₆ alkyl group,    -   (i) a halo C₁₋₆ alkoxy group,    -   (j) a hydroxy C₁₋₆ alkoxy group,    -   (k) a C₁₋₆ alkoxy C₁₋₆ alkoxy group,    -   (l) a carboxy C₁₋₆ alkoxy group,    -   (m) a C₆₋₁₀ aryl C₁₋₆ alkoxy group,    -   (n) a C₁₋₆ alkylsulfanyl C₁₋₆ alkoxy group,    -   (o) a C₁₋₆ alkylsulfonyl C₁₋₆ alkoxy group,    -   (p) a C₆₋₁₀ aryl C₁₋₆ alkoxy C₁₋₆ alkoxy group,    -   (q) a saturated heterocyclo C₁₋₆ alkoxy group (the saturated        heterocycle is of 4-membered to 6-membered saturated heterocycle        having 1 to 2 heteroatoms selected from nitrogen, oxygen, and        sulfur, and is optionally substituted by 1 to 2 C₁₋₆ alkyl        groups),    -   (r) a saturated heterocyclo oxy group (the saturated heterocycle        is a 4-membered to 6-membered saturated heterocycle having 1 to        2 heteroatoms selected from nitrogen, oxygen, and sulfur),    -   (s) a C₃₋₈ cycloalkyloxy group,    -   (t) a C₁₋₆ alkoxycarbonyloxy group and    -   (u) a C₁₋₆ alkylsulfonyl group), or        (10) a saturated heterocycle group (the saturated heterocycle is        of 4-membered to 6-membered saturated heterocycle having 1 to 2        heteroatoms selected from nitrogen, oxygen, and sulfur, and is        optionally substituted by 1 to 4 C₁₋₆ alkyl groups), and        Ring Cy^(a) is a group selected from        (1) a group represented by the Formula:

whereinm2 is 1, 2 or 3,m3 is 1, 2 or 3,n3 is 1 or 2,(2) a group represented by the Formula:

whereinm4 is 0, 1, 2 or 3,m5 is 0, 1 or 2,provided sum of m4 and m5 is 1 or more,(3) a group represented by the Formula:

whereinm4 is 0, 1, 2 or 3,m5 is 0, 1 or 2,provided sum of m4 and m5 is 1 or more,(4) a group represented by the Formula:

whereinm6 is 0, 1 or 2,m7 is 0, 1 or 2,provided sum of m6 and m7 is 1 or more,(5) a group represented by the Formula:

whereinm6 is 0, 1 or 2,m7 is 0, 1 or 2,provided sum of m6 and m7 is 1 or more,(6) a group represented by the Formula:

whereinm8 is 1 or 2,m9 is 1 or 2, and(7) a group represented by the Formula:

whereinm8 is 1 or 2,m9 is 1 or 2,n2 is 0, 1, 2, 3 or 4,

R^(3a) is

(1) hydroxy,(2) a C₁₋₆ alkyl group or(3) a hydroxy C₁₋₆ alkyl group,provided when n2 is 2, 3 or 4, R^(3a) each is the same or different,

R^(3b) is

(1) hydroxy,(2) a C₁₋₆ alkyl group (which optionally form a C₃₋₆ cycloalkyl grouptogether with the carbon to which it is attached and the carbon adjacentthereto) or(3) a hydroxy C₁₋₆ alkyl group, or(4) when two R^(3b) are attached to the same carbon, they optionallyform a C₃₋₆ cycloalkyl group together with the carbon to which they areattached,provided, when n2 is 2, 3 or 4, each R^(3b) is the same or different,and

R^(4b) is

-   -   (1) a hydrogen atom,    -   (2) a C₁₋₆ alkyl group,    -   (3) a carboxy C₁₋₆ alkyl group,    -   (4) a halo C₁₋₆ alkyl group or    -   (5) a C₁₋₆ alkoxy C₁₋₆ alkyl group.

Paragraph 21: The compound or a pharmaceutically acceptable salt thereofaccording to paragraph 20, wherein

Ring Cy^(a) is selected from(1) a group represented by the Formula:

whereinm4 is 0, 1, 2 or 3,m5 is 0, 1 or 2,provided sum of m4 and m5 is 1 or more,(2) a group represented by the Formula:

whereinm6 is 0, 1 or 2,m7 is 0, 1 or 2,provided sum of m6 and m7 is 1 or more,(3) a group represented by the Formula:

whereinm6 is 0, 1 or 2,m7 is 0, 1 or 2,provided sum of m6 and m7 is 1 or more,(4) a group represented by the Formula:

whereinm8 is 1 or 2,m9 is 1 or 2, and(5) a group represented by the Formula:

whereinm8 is 1 or 2,m9 is 1 or 2,n2 is 0, 1, 2, 3 or 4,

R^(3a) is

(1) hydroxy,(2) a C₁₋₆ alkyl group or(3) a hydroxy C₁₋₆ alkyl group,provided when n2 is 2, 3 or 4, each R^(3a) is the same or different,

R^(3b) is

(1) hydroxy,(2) a C₁₋₆ alkyl group (which optionally form a C₃₋₆ cycloalkyl grouptogether with the carbon to which it is attached and the carbon adjacentthereto) or(3) a hydroxy C₁₋₆ alkyl group, or(4) when two R^(3b) are attached to the same carbon, they optionallyform a C₃₋₆ cycloalkyl group together with the carbon to which they areattached,provided, when n2 is 2, 3 or 4, each R^(3b) is the same or different,and

R^(4b) is

(1) a hydrogen atom,(2) a C₁₋₆ alkyl group,(3) a carboxy C₁₋₆ alkyl group,(4) a halo C₁₋₆ alkyl group or(5) a C₁₋₆ alkoxy C₁₋₆ alkyl group.

Paragraph 22: The compound or a pharmaceutically acceptable salt thereofaccording to paragraph 20, wherein

Ring Cy^(a) is selected from(1) a group represented by the Formula:

wherein,m4 is 0, 1, 2 or 3,m5 is 0, 1 or 2,provided sum of m4 and m5 is 1 or more, and(2) a group represented by the Formula:

whereinm6 is 0, 1 or 2,m7 is 0, 1 or 2,provided sum of m6 and m7 is 1 or more, n2 is 0, 1, 2, 3 or 4,

R^(3a) is

(1) hydroxy,(2) a C₁₋₆ alkyl group or(3) a hydroxy C₁₋₆ alkyl group,provided, when n2 is 2, 3 or 4, each R^(3a) is the same or different,

R^(3b) is

(1) hydroxy,(2) a C₁₋₆ alkyl group (which optionally form a C₃₋₆ cycloalkyl grouptogether with the carbon to which it is attached and the carbon adjacentthereto) or(3) a hydroxy C₁₋₆ alkyl group, or(4) when two R^(3b) are attached to the same carbon, they optionallyform a C₃₋₆ cycloalkyl group together with the carbon to which they areattached,provided, when n2 is 2, 3 or 4, each R^(3b) is the same or different,and

R^(4b) is

(1) a hydrogen atom,(2) a C₁₋₆ alkyl group.(3) a carboxy C₁₋₆ alkyl group,(4) a halo C₁₋₆ alkyl group or(5) a C₁₋₆ alkoxy C₁₋₆ alkyl group.

Paragraph 23: The compound or a pharmaceutically acceptable salt thereofaccording to paragraph 20, wherein

Ring Cy^(a) is selected from(1) a group represented by the Formula:

whereinn2 is 0, 1, 2, 3 or 4, and(2) a group represented by the Formula:

whereinn2 is 0 or 1,

R^(3a) is

(1) hydroxy,(2) a C₁₋₆ alkyl group or(3) a hydroxy C₁₋₆ alkyl group, and

R^(3b) is

(1) hydroxy,(2) a C₁₋₆ alkyl group (which optionally form a C₃₋₆ cycloalkyl grouptogether with the carbon to which it is attached and the carbon adjacentthereto) or(3) a hydroxy C₁₋₆ alkyl group, or(4) when two R^(3b) are attached to the same carbon, they optionallyform a C₃₋₆ cycloalkyl group together with the carbon to which they areattached,provided, when n2 is 2, 3 or 4, each R^(3b) is the same or different,and

R^(4b) is

(1) a hydrogen atom,(2) a C₁₋₆ alkyl group,(3) a carboxy C₁₋₆ alkyl group,(4) a halo C₁₋₆ alkyl group or(5) a C₁₋₆ alkoxy C₁₋₆ alkyl group.

Paragraph 24: The compound or a pharmaceutically acceptable salt thereofaccording to any one of paragraphs 20 to 23, wherein the ring Cy isC₆₋₁₀ aryl.

Paragraph 25: The compound or a pharmaceutically acceptable salt thereofaccording to paragraph 24, wherein the ring Cy is phenyl.

Paragraph 26: The compound or a pharmaceutically acceptable salt thereofaccording to any one of paragraphs 20 to 25 wherein R^(1a) is

(1) a halogen atom,(2) a C₁₋₆ alkyl group,(3) a C₁ 6 alkoxy group,(4) a halo C₁₋₆ alkyl group,(5) a C₁₋₆ alkoxy C₁₋₆ alkyl group,(6) a halo C₁₋₆ alkoxy C₁₋₆ alkyl group or(7) a halo C₁₋₆ alkoxy group,provided when n1 is 2, 3, or 4, R^(1a) each is the same or different.

Paragraph 27: The compound or a pharmaceutically acceptable salt thereofaccording to any one of paragraphs 20 to 26,

wherein R^(2a) is a C₆₋₁₀ aryl group (the C₆₋₁₀ aryl group is optionallysubstituted by 1 to 4 substituents selected from(a) a halogen atom,(b) a C₁₋₆ alkyl group,(c) a C₁₋₆ alkoxy group and(d) a carboxy C₁₋₆ alkoxy group).

Paragraph 28: The compound or a pharmaceutically acceptable salt thereofaccording to paragraph 27,

wherein R^(2a) is a phenyl group (the phenyl group is optionallysubstituted by 1 to 4 substituents selected from(a) a halogen atom,(b) a C₁₋₆ alkyl group,(c) a C₁₋₆ alkoxy group and(d) a carboxy C₁₋₆ alkoxy group).

Paragraph 29: The compound or pharmaceutically acceptable salt thereofof paragraph 20, wherein the compound is selected from the followingFormulae:

Paragraph 30: A pharmaceutical composition which comprises a compound ora pharmaceutically acceptable salt thereof according to any one ofparagraphs 20 to 29 and a pharmaceutically acceptable carrier.

Paragraph 31: A SGLT1 inhibitor which comprises a compound or apharmaceutically acceptable salt thereof according to any one ofparagraphs 20 to 29.

Paragraph 32: An agent for treating or preventing diabetes whichcomprises a compound or a pharmaceutically acceptable salt thereofaccording to any one of paragraphs 20 to 29.

Paragraph 33: The agent for treating or preventing diabetes according toparagraph 32, wherein diabetes is type II diabetes mellitus.

Paragraph 34: A method for inhibiting SGLT1 which comprisesadministrating to mammals a therapeutically effective amount of acompound or a pharmaceutically acceptable salt thereof according to anyone of paragraphs 20 to 29.

Paragraph 35: A method for treating or preventing diabetes whichcomprises administrating to mammals a therapeutically effective amountof a compound or a pharmaceutically acceptable salt thereof according toany one of paragraphs 20 to 29.

Paragraph 36: The method according to paragraph 35, wherein the diabetesis type II diabetes mellitus.

Paragraph 37: Use of a compound or a pharmaceutically acceptable saltthereof according to any one of paragraphs 20 to 29 for manufacturing aSGLT1 inhibitor.

Paragraph 38: Use of a compound or a pharmaceutically acceptable saltthereof according to any one of paragraphs 20 to 29 for manufacturing anagent for treating or preventing diabetes.

Paragraph 39: The use according to paragraph 38 wherein the diabetes istype II diabetes mellitus.

Paragraph 40: A kit for commerce comprising

(a) a pharmaceutical composition which comprises a compound or apharmaceutically acceptable salt thereof according to any one ofparagraphs 20 to 29 as an active ingredient, and(b) a package insert about the pharmaceutical composition whichindicates that the pharmaceutical composition can be used or should beused for treatment or prevention of type II diabetes mellitus.

Paragraph 41: A package for commerce comprising

(a) a pharmaceutical composition which comprises a compound or apharmaceutically acceptable salt thereof according to any one ofparagraphs 20 to 29 as an active ingredient, and(b) a package insert about the pharmaceutical composition whichindicates that the pharmaceutical composition can be used or should beused for treatment or prevention of type II diabetes mellitus.

Effect of the Invention

Since the pyrazole compound or a pharmaceutically acceptable saltthereof in the present invention has SGLT1 inhibitory activity, it isuseful for the treatment and/or prevention of diabetes, obesity,diabetic complications (for example, retinopathy, nephropathy andneuropathy which are known as microangiopathy, as well ascerebrovascular disease, ischemic heart disease and membrum-inferiusarteriosclerosis obliterans which are known as macroangiopathy),hypertrophic cardiomyopathy, ischemic heart disease, cancer andconstipation.

BEST MODE FOR CARRYING OUT THE INVENTION

The definitions of the terms in this description are as follows.

The term “optionally substituted” includes both of cases where thereplaceable positions of an intended group are substituted and notsubstituted (non-substituted). Here, the term “non-substituted” meansthe case where all the replaceable positions of an intended group areoccupied with hydrogen atoms.

For example, the term “optionally substituted by 1 to 4 C₁₋₆ alkylgroups” includes both of cases wherein the replaceable positions of anintended group are substituted by 1-4 C₁₋₆ alkyl groups and notsubstituted (non-substituted), and each substituent may be the same ordifferent.

Unless otherwise specified, an explanation of each group is applied tothe case wherein the group is a moiety of other groups or a substituent.

A “halogen atom” includes, for example, fluorine atom, chlorine atom,bromine atom and iodine atom.

Preferable one is fluorine atom or chlorine atom.

A “C₁₋₈ alkyl” group means a saturated hydrocarbon group of a straightchain or a branched chain having 1-8 carbon atoms, and the term “C₁₋₆alkyl” group means the saturated hydrocarbon group of a straight chainor a branched chain having 1-6 carbon atoms.

Among this group, for example, methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,2-methylpropyl, 1,1-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutylare included.

Preferable one is C₁₋₆ alkyl group. More preferable are methyl, ethyl,propyl, isopropyl, n-butyl, tert-butyl, isopentyl, 2-methylpropyl,1,1-dimethylpropyl, hexyl, and 3,3-dimethylbutyl.

Especially preferable are methyl, ethyl, propyl, n-butyl, and isopentyl.

A “C₂₋₈ alkenyl” group means a hydrocarbon group having at least onedouble bond of a straight chain or a branched chain having 2-8 carbonatoms.

As this group, for example vinyl, 1-propenyl, 2-propenyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl,1-ethylvinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-1-butenyl, 1-isopropylvinyl, 2,4-pentadienyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl,1-methyl-1-pentenyl, 3,3-dimethylbutenyl (namely, 3,3-dimethylbut-1-eneyl), are mentioned.

Preferable one is C₂₋₆ alkenyl group. More preferable are 1-propenyl,2-methyl-1-propenyl, and 3,3-dimethyl but-1-eneyl.

A “C₂₋₆ alkynyl” group means a hydrocarbon group which has at least onetriple bond of a straight chain or a branched chain having 2-6 carbonatoms, and “C₂₋₈ alkynyl group” means a hydrocarbon group having atleast one triple bond of a straight chain or a branched chain having 2-8carbon atoms. Specifically, ethynyl, 1-propynyl, 2-propynyl,isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-1-propynyl,1-methyl-2-propynyl, 2-methyl-2-propynyl, 1-ethylethynyl,3,3-dimethylbutynyl (namely, 3,3-dimethyl but-1-yneyl), are mentioned.

Preferable one is C₂₋₆ alkynyl group. More preferable is 3,3-dimethylbut-1-yneyl.

A “C₁₋₆ alkoxy” group means an alkoxy group with a straight chain or abranched chain of 1-6 carbon atoms.

Among this group, for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,2-methylbutoxy, 1,1-dimethylpropoxy, neopentyl oxy, 3,3-dimethylbutoxy,1-ethylpropoxy and hexyloxy are included.

Preferable one is C₁₋₄ alkoxy group. More preferable are methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,isopentyloxy (namely, 3-methylbutoxy), neopentyl oxy (namely,2,2-dimethylpropoxy), 1,1-dimethylpropoxy, and 3,3-dimethylbutoxy.

A “C₆₋₁₀ aryl” group means an aromatic hydrocarbon group having 6-10carbon atoms. Among this group, for example, phenyl, 1-naphthyl and2-naphthyl are included.

Preferable one is phenyl.

A “C₃₋₈ cycloalkyl” group means a monocycle saturated hydrocarbon grouphaving 3-8 carbon atoms, and the “C₃₋₆ cycloalkyl” group means themonocycle saturated hydrocarbon group having 3-6 carbon atoms.

Among this group, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl are included.

Preferable one is C₃₋₇ cycloalkyl group. More preferable is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

A “C₃₋₈ cycloalkenyl” group means a monocycle unsaturated hydrocarbongroup having 3-8 carbon atoms including one or more double bonds.

Among this group, for example, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl areincluded. Preferable one is C₃₋₆ cycloalkenyl group. More preferable iscyclohexenyl. Especially preferable is 1-cyclohexenyl.

A “saturated heterocycle” group means a group having a 4 to 6-memberedring containing 1 to 2 heteroatoms selected from nitrogen, oxygen, andsulfur in addition to a carbon atom, and whose atomic numbersconstituting the ring are 4 to 6, preferably 5 to 6.

Among this group, for example, pyrrolidinyl, pyrrolidino (1-pyrrolidinyletc.), piperidinyl, piperidino (1-piperidinyl etc.), morpholinyl,morpholino (4-morpholinyl etc.), thiomorpholinyl, thiomorpholino(4-thiomorpholinyl etc.), piperazinyl, piperazino (1-piperazinyl etc.),tetrahydropyranyl ((R)-tetrahydropyran-3-yl, (S)-tetrahydropyran-3-yletc.), tetrahydrofuranyl ((R)-tetrahydrofuran-3-yl,(S)-tetrahydrofuran-3-yl, etc.), oxetanyl, etc. are included.

Preferable one is a saturated heterocycle group with 5 to 6 membershaving in its ring containing one heteroatom selected from a nitrogenatom or an oxygen atom in addition to a carbon atom. More preferable aretetrahydropyranyl, tetrahydrofuranyl, oxetanyl and pyrrolidinyl.Especially preferable are (R)-tetrahydropyran-3-yl,(S)-tetrahydropyran-3-yl, 4-tetrahydropyranyl, (R)-tetrahydrofuran-3-yl,(S)-tetrahydrofuran-3-yl, oxetane-3-yl, and 1-pyrrolidinyl.

A “halo C₁₋₆ alkyl” group means “C₁₋₆ alkyl” group of theabove-mentioned definition substituted by 1 to 13 “halogen atoms” of theabove-mentioned definition. When multiple halogen atoms substitute, eachhalogen atom is the same or different. Preferable one is a group whichis substituted with 1 to 6 “halogen atoms”. More preferable is the groupwhich is substituted with 1 to 6 fluorine atoms.

Among this group, for example, 2-fluoroethyl, 2-chloroethyl,2-bromoethyl, 3-fluoropropyl, 3-chloropropyl, 4-fluorobutyl,4-chlorobutyl, 1,1-difluoroethyl, 1,1-difluoropropyl,1,1-difluoro-2-methylpropyl, trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, pentafluoroethyl and2,2,2-trifluoro-1-trifluoromethylethyl are included.

Preferable one is halo C₁₋₄ alkyl group. More preferable is1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluoro-2-methylpropyl,trifluoromethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.

A “hydroxy C₁₋₆ alkyl” group means a group in which the hydroxy group(s)is mono- or di-substituted on the “C₁₋₆ alkyl” group of theabove-mentioned definition. Preferable one is a group which ismono-substituted by hydroxyl group.

Among this group, for example, hydroxymethyl, 2-hydroxyethyl,1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl,1-hydroxy-2,2-dimethylpropyl, 4-hydroxybutyl,1-hydroxy-2,2-dimethylbutyl, 5-hydroxypentyl and 6-hydroxyhexyl areincluded.

Preferable one is hydroxy C₁₋₄ alkyl group. More preferable arehydroxymethyl, 2-hydroxyethyl, and 1-hydroxy-1-methylethyl,1-hydroxy-2,2-dimethylpropyl and 1-hydroxy-2,2-dimethylbutyl.

A “C₁₋₆ alkoxy C₁₋₆ alkyl” group means a group in which the “C₁₋₆alkoxy” group(s) of the above-mentioned definition is mono- ordi-substituted on the “C₁₋₆ alkyl” group of the above-mentioneddefinition. When the C₁₋₆ alkoxy groups are di-substituted, each C₁₋₆alkoxy group is the same or different.

Among this group, for example, methoxymethyl, ethoxymethyl,n-propoxymethyl, isopropoxymethyl, isobutoxymethyl, tert-butoxymethyl,(R)-sec-butoxymethyl, (S)-sec-butoxymethyl, 2-methoxyethyl,(R)-1-propoxyethyl, (S)-1-propoxyethyl, 1-ethylpropoxymethyl,1-methoxy-1-methylethyl, 1,2-dimethoxyethyl, 2,2-dimethylpropoxymethyl,2-methoxy-1,1-dimethylethyl, 1-methyl-1-propoxy-ethyl,2-isopropoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2,3-diethoxypropyl,4-methoxybutyl, 5-methoxypentyl, 5-ethoxypentyl, 6-methoxyhexyl,6-ethoxyhexyl, pentyloxymethyl and hexyloxymethyl are included.

Preferable one is C₁₋₄ alkoxy C₁₋₃ alkyl group. More preferable aremethoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl,isobutoxymethyl, 1-methoxy-1-methylethyl, 2-isopropoxyethyl,tert-butoxymethyl, (R)-sec-butoxymethyl, (S)-sec-butoxymethyl,1-ethylpropoxymethyl, (R)-1-propoxyethyl, (S)-1-propoxyethyl,1-ethoxy-1-methylethyl, 1-methoxy-1-methylethyl,2,2-dimethylpropoxymethyl, 2-methoxy-1,1-dimethylethyl, and1-methyl-1-propoxy-ethyl.

A “C₃₋₈ cycloalkyl C₁₋₆ alkyl” group means a group in which “C₃₋₈cycloalkyl” group(s) of the above-mentioned definition is mono- ordi-substituted on the “C₁₋₆ alkyl” group of the above-mentioneddefinition.

When the C₃₋₈ cycloalkyl groups are di-substituted, each C₃₋₈ cycloalkylgroup is the same or different.

Among this group, for example, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclooctylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl,2-cycloheptylethyl, 2-cyclooctylethyl, 3-cyclopropylpropyl,3,3-dicyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl,2-cyclohexylpropyl, 3-cyclohexylpropyl, 3-cycloheptylpropyl,3-cyclooctylpropyl, 4-cyclopropylbutyl, 4-cyclobutylmethyl,4-cyclopentylbutyl, 4-cyclohexylbutyl, 4-cycloheptylbutyl,4-cyclooctylbutyl, 5-cyclopropylpentyl, 5-cyclobutylpentyl,3-cyclopentylpentyl, 5-cyclopentylpentyl, 5-cyclohexylpentyl,5-cycloheptylpentyl, 5-cyclooctylpentyl, 6-cyclopropylhexyl,6-cyclobutylhexyl, 6-cyclopentylhexyl, 6-cyclohexylhexyl,6-cycloheptylhexyl and 6-cyclooctylhexyl are included.

Preferable one is C₃₋₆ cycloalkyl C₁₋₃ alkyl group. More preferable arecyclohexylmethyl, 2-cyclopentylethyl and 2-cyclohexylethyl.

A “C₃₋₆ cycloalkyl C₂₋₆ alkynyl” group means a group to which “C₃₋₆cycloalkyl” group(s) of the above-mentioned definition is mono- ordi-substituted on the “C₂₋₆ alkynyl” group of the above-mentioneddefinition. When the C₃₋₆ cycloalkyl groups are di-substituted, eachC₃₋₆ cycloalkyl group is the same or different. A Preferable group is aC₂₋₆ alkynyl group mono-substituted by the C₃₋₆ cycloalkyl group.

As this group, for example, cyclopropylethynyl, cyclobutylethynyl,cyclopentylethynyl, cyclohexylethynyl, cyclopropyl-1-propynyl, arementioned.

Preferable one is C₃₋₆ cycloalkyl C₂₋₄ alkynyl. More preferable iscyclopropylethynyl.

A “C₆₋₁₀ aryl C₁₋₆ alkyl” group means a group in which the “C₆₋₁₀ aryl”group(s) of the above-mentioned definition is mono- or di-substituted onthe “C₁₋₆ alkyl” group of the above-mentioned definition.

When the C₆₋₁₀ aryl groups are di-substituted, each C₆₋₁₀ aryl group isthe same or different.

Among this group, for example, benzyl, naphthylmethyl, 1-phenylethyl,2-phenylethyl, 2-naphthylethyl and 3,3-diphenylpropyl are included.

Preferable one is C₆₋₁₀ aryl C₁₋₃ alkyl group. More preferable arebenzyl and 2-phenylethyl.

A “saturated heterocyclo C₁₋₆ alkyl” group means a group in which“saturated heterocyclo” group(s) of the above-mentioned definition ismono- or di-substituted on the “C₁₋₆ alkyl” group of the above-mentioneddefinition. When the saturated heterocycle groups are di-substituted,each saturated heterocycle group is the same or different.

Among this group, for example, (1-pyrrolidinyl)methyl (namelypyrrolidine-1-ylmethyl), (1-piperidinyl)methyl, (4-morpholinyl)methyl,(4-thiomorpholinyl)methyl, (1-piperazinyl)methyl,(4-tetrahydropyranyl)methyl, 2-(1-pyrrolidinyl)ethyl,2-(1-piperidinyl)ethyl, 2-(4-morpholinyl)ethyl,2-(4-thiomorpholinyl)ethyl, 2-(1-piperazinyl)ethyl,2-(4-tetrahydropyranyl)ethyl and 2-(4-tetrahydropyranyl)propyl areincluded.

Preferable one is a saturated heterocyclo C₁₋₃ alkyl group. Morepreferable are (4-tetrahydropyranyl)methyl, pyrrolidine-1-ylmethyl,2-(1-pyrrolidinyl)ethyl and 2-(4-tetrahydropyranyl)ethyl.

A “halo C₁₋₆ alkoxy” group means a group having 1 to 13 “halogen atoms”of the above-mentioned definition substituted on the “C₁₋₆ alkoxy” groupof the above-mentioned definition. When multiple halogen atoms aresubstituted, each halogen atom is the same or different. Preferable oneis a group which is substituted by 1 to 6 “halogen atoms”. Morepreferable is a group which is substituted by 1 to 6 fluorine atoms.

Among this group, for example, fluoromethoxy, chloromethoxy,bromomethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy,3-fluoropropoxy, 3-chloropropoxy, 4-fluorobutoxy, 4-chlorobutoxy,1,1-difluoroethoxy, 2,2-difluoroethoxy, 1,1-difluoropropoxy,2,2-difluoropropoxy, 3,3-difluoropropoxy, 1,1-difluoro-2-methylpropoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy,4,4,4-trifluorobutoxy, pentafluoroethoxy and2,2,2-trifluoro-1-trifluoromethylethoxy are included.

Preferable one is halo C₁₋₄ alkoxy group. Another preferable group ishalo C₁₋₆ alkoxy group whose halogens are 1 to 3 fluorine atoms. Morepreferable are trifluoromethoxy, 2,2,2-trifluoroethoxy and3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, and2,2,2-trifluoro-1-trifluoromethylethoxy.

A “hydroxy C₁₋₆alkoxy” group means a group in which the hydroxy group(s)is mono- or di-substituted on the “C₁₋₆ alkoxy” group of theabove-mentioned definition. Preferable one is a group which ismono-substituted by hydroxy group.

As this group, for example, hydroxymethoxy, 2-hydroxyethoxy,1-hydroxy-1-methylethoxy, 1,2-dihydroxyethoxy, 3-hydroxypropoxy,1-hydroxy-2,2-dimethylpropoxy, 4-hydroxybutoxy,1-hydroxy-2,2-dimethylbutoxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, arementioned.

Preferable one is hydroxy C₁₋₄ alkoxy group. More preferable is2-hydroxyethoxy.

A “carboxy C₁₋₆ alkoxy” group means a group in which carboxy(s) is mono-or di-substituted on the “C₁₋₆ alkoxy” group of the above-mentioneddefinition. Preferable one is a group which is mono-substituted by acarboxy.

Among this group, for example, carboxymethoxy, 2-carboxyethoxy,3-carboxypropoxy, 2-carboxy-1-methylethoxy, 4-carboxybutoxy,5-carboxypentyloxy and 6-carboxyhexyloxy are included.

Preferable one is carboxy C₁₋₄ alkoxy group. More preferable iscarboxymethoxy.

A “C₁₋₆ alkoxy C₁₋₆ alkoxy” group means a group in which the “C₁₋₆alkoxy” of the above-mentioned definition is mono- or di-substituted onthe “C₁₋₆ alkoxy” group of the above-mentioned definition. When the C₁₋₆alkoxy groups are di-substituted, each C₁₋₆ alkoxy group is the same ordifferent.

As this group, for example, methoxymethoxy, ethoxymethoxy,n-propoxymethoxy, isobutoxymethoxy, tert-butoxymethoxy,(R)-sec-butoxymethoxy, (S)-sec-butoxymethoxy, 2-methoxyethoxy,(R)-1-propoxyethoxy, (S)-1-propoxyethoxy, 1-ethylpropoxyethoxy,1-methoxy-1-methylethoxy, 1,2-dimethoxyethoxy,2,2-dimethylpropoxymethoxy, 2-methoxy-1,1-dimethylethoxy,1-methyl-1-propoxy-ethoxy, 2-isopropoxyethoxy, 3-methoxypropoxy,3-ethoxypropoxy, 2,3-diethoxypropoxy, 4-methoxybutoxy,5-methoxypentyloxy, 5-ethoxypentyloxy, 6-methoxyhexyloxy,6-ethoxyhexyloxy, pentyloxymethoxy, hexyloxymethoxy, are mentioned.

Preferable one is C₁₋₃ alkoxy C₂₋₄ alkoxy group. More preferable is2-methoxyethoxy.

A “C₆₋₁₀ aryl C₁₋₆ alkoxy” group means a group in which the “C₆₋₁₀ aryl”group of the above-mentioned definition is mono- or di-substituted onthe “C₁₋₆ alkoxy” group of the above-mentioned definition. When theC₆₋₁₀ aryl groups are di-substituted, each C₆₋₁₀ aryl group is the sameor different. As this group, benzyloxy, naphthlmethyloxy,1-phenylethyloxy, 2-phenylethyloxy, 2-naphthylethyloxy,3,3-diphenylpropoxy, are mentioned, for example.

Preferable one is C₆₋₁₀ aryl C₁₋₃ alkyl group. More preferably it isbenzyloxy.

A “halo C₁₋₆ alkoxy C₁₋₆ alkyl” group means a group in which the “haloC₁₋₆ alkoxy” group of the above-mentioned definition is mono- ordi-substituted on the “C₁₋₆ alkyl” group of the above-mentioneddefinition. When the halo C₁₋₆ alkoxy groups are di-substituted, eachhalo C₁₋₆ alkoxy group is the same or different.

As this group, for example fluoromethoxymethyl, chloromethoxymethyl,bromomethoxymethyl, 2-fluoroethoxymethyl, 2-chloroethoxymethyl,2-bromoethoxymethyl, 3-fluoropropoxymethyl, 3-chloropropoxymethyl,4-fluorobutoxymethyl, 4-chlorobutoxymethyl, 1,1-difluoroethoxymethyl,2,2-difluoroethoxymethyl, 1,1-difluoropropoxymethyl,2,2-difluoropropoxymethyl, 3,3-difluoropropoxymethyl,1,1-difluoro-2-methylpropoxymethyl, trifluoromethoxymethyl, 2,3-bistrifluoromethoxypropyl, 2,2,2-trifluoroethoxymethyl,3,3,3-trifluoropropoxymethyl, 4,4,4-trifluorobutoxymethyl,pentafluoroethoxymethyl, 2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl,1-(trifluoromethoxy)ethyl, 1-methyl-2,3-bis-trifluoromethoxypropyl,1-(2,2,2-trifluoroethoxy)ethyl, 1-(3,3,3-trifluoropropoxy)ethyl,1-(4,4,4-trifluorobutoxy)ethyl,1-(2,2,2-trifluoro-1-trifluoromethylethoxy)ethyl,2-(trifluoromethoxy)ethyl, 2-(2,2,2-trifluoroethoxy)ethyl,2-(3,3,3-trifluoropropoxy)ethyl, 2-(4,4,4-trifluorobutoxy)ethyl,2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)ethyl,1-methyl-1-(trifluoromethoxy)ethyl,1-methyl-1-(2,2,2-trifluoroethoxy)ethyl,1-methyl-1-(3,3,3-trifluoropropoxy)ethyl,1-methyl-1-(4,4,4-trifluorobutoxy)ethyl,1-methyl-1-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)ethyl,(R)-2,2,2-trifluoro-1-methylethoxymethyl,(S)-2,2,2-trifluoro-1-methylethoxymethyl,2,2,2-trifluoro-1,1-dimethyl-ethoxymethyl,2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl,2,2,2-trifluoro-1-methyl-1-trifluoromethyl-ethoxymethyl,3,3,3-trifluoro-2-(trifluoromethyl)propoxymethyl,4,4,4-trifluoro-3-(trifluoromethyl)butoxymethyl,1,1-dimethyl-3,3,3-trifluoropropoxymethyl,2,2-dimethyl-3,3,3-trifluoropropoxymethyl,4,4,4-trifluoro-3-(trifluoromethyl)butoxymethyl,1,1-dimethyl-4,4,4-trifluorobutoxymethyl,2,2-dimethyl-4,4,4-trifluorobutoxymethyl,3-methyl-4,4,4-trifluoro-3-(trifluoromethyl)-butoxymethyl,2-methyl-3,3,3-trifluoro-2-trifluoromethyl-propoxymethyl, are mentioned.

Preferable one is halo C₁₋₄ alkoxy C₁₋₃ alkyl group. More preferable aretrifluoromethoxymethyl, 2,2,2-trifluoroethoxymethyl,3,3,3-trifluoropropoxymethyl, (R)-2,2,2-trifluoro-1-methylethoxymethyl,(S)-2,2,2-trifluoro-1-methylethoxymethyl,2,2,2-trifluoro-1,1-dimethyl-ethoxymethyl,2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl and2,2,2-trifluoro-1-methyl-1-trifluoromethyl-ethoxymethyl.

A “halo C₃₋₈ cycloalkyl” group means a group in which 1 to 15 “halogenatoms” of the above-mentioned definition is substituted on the “C₃₋₈cycloalkyl” group of the above-mentioned definition: A preferable groupis a group which is substituted by 1 to 2 “halogen atoms”.

When multiple halogen atoms are substituted, each halogen atom may bethe same or different.

Among this group, for example, 2-fluorocyclopropyl, 2-chlorocyclopropyl,3-fluorocyclobutyl, 3-chlorocyclobutyl, 3-fluorocyclopentyl,3-chlorocyclopentyl, 4-fluorocyclohexyl, 4-fluorocycloheptyl,5-fluorocyclooctyl, 2,2-difluorocyclopropyl, 2,2-dichlorocyclopropyl,3,3-difluorocyclobutyl, 3,3-dichlorocyclobutyl, 3,3-difluorocyclopentyl,3,3-dichlorocyclopentyl, 4,4-difluorocyclohexyl and4,4-dichlorocyclohexyl are included.

Preferable one is halo C₃₋₆ cycloalkyl group. Another preferable groupis halo C₃₋₈ cycloalkyl group whose halogen atoms are 1 to 3 fluorineatoms. More preferable is 4,4-difluorocyclohexyl.

A “C₁₋₆ alkyl sulfanyl” group means the sulfanyl group substituted bythe “C₁₋₆ alkyl” group of the above-mentioned definition.

As this group, for example methylsulfanyl, ethylsulfanyl,propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl,sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl,1,1-dimethylpropylsulfanyl, 2,2-dimethylpropylsulfanyl, hexylsulfanyl,are mentioned.

Preferable one is isobutylsulfanyl.

A “C₁₋₆ alkyl sulfonyl” group means a sulfonyl group substituted by the“C₁₋₆ alkyl” group of the above-mentioned definition.

As this group, for example, methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl (namely, propane-2-sulfonyl),n-butylsulfonyl, isobutylsulfonyl (namely, 2-methylpropane-1-sulfonyl),sec-butylsulfonyl, tert-butylsulfonyl (namely,2-methyl-propane-2-sulfonyl), pentylsulfonyl,1,1-dimethylpropylsulfonyl, hexylsulfonyl, 2,2-dimethylpropylsulfonyl(namely, 2,2-dimethylpropane-1-sulfonyl), are mentioned.

Preferable are propane-2-sulfonyl, 2-methylpropane-1-sulfonyl,2-methyl-propane-2-sulfonyl, and 2,2-dimethylpropane-1-sulfonyl.

A “halo C₁₋₆ alkyl sulfonyl” group means a sulfonyl group substituted bythe “halo C₁₋₆ alkyl” group of the above-mentioned definition.

As this group, for example, 2-fluoroethanesulfonyl,2-chloroethanesulfonyl, 2-bromoethanesulfonyl, 3-fluoropropanesulfonyl,3-chloropropanesulfonyl, 4-fluorobutanesulfonyl, 4-chlorobutanesulfonyl,1,1-difluoroethanesulfonyl, 1,1-difluoropropanesulfonyl,1,1-difluoro-2-methylpropanesulfonyl, trifluoromethanesulfonyl,2,2,2-trifluoroethanesulfonyl, 3,3,3-trifluoropropanesulfonyl,4,4,4-trifluorobutanesulfonyl, pentafluoroethanesulfonyl,2,2,2-trifluoro-1-trifluoromethyl ethanesulfonyl, are mentioned.

Preferable are 2,2,2-trifluoro ethanesulfonyl and3,3,3-trifluoropropanesulfonyl.

A “C₁₋₈ alkyl carbonyl” group means a carbonyl group substituted by the“C₁₋₈ alkyl” group of the above-mentioned definition.

As this group, acetyl, propionyl, 2,2-dimethylpropionyl, butyryl,3-methylbutyryl, 2,2-dimethylbutyryl, pentanoyl, 4-methylpentanoyl,3,4-dimethylpentanoyl, heptanoyl, nonanoyl, are mentioned, for example.

Preferable are 2,2-dimethylbutyryl and 2,2-dimethylpropionyl.

A “C₁₋₆ alkyloxy carbonyl” group means a carbonyl group substituted bythe “C₁₋₆ alkoxy” group of the above-mentioned definition.

As this group, for example methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, 2-methylbutoxycarbonyl,1,1-dimethylpropoxycarbonyl, neopentyloxycarbonyl,3,3-dimethylbutoxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl,are mentioned.

A “C₁₋₆ alkoxy carbonyloxy” group means a carbonyloxy group substitutedby the “C₁₋₆ alkoxy” group of the above-mentioned definition.

As this group, for example methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, isopropoxycarbonyloxy, buthoxycarbonyloxy,isobuthoxycarbonyloxy, sec-buthoxycarbonyloxy, tert-buthoxycarbonyloxy,pentyloxycarbonyloxy, isopentyloxycarbonyloxy, 2-methylbuthoxycarbonyloxy, 1,1-dimethylpropoxycarbonyloxy,neopentyloxycarbonyloxy, 3,3-dimethyl buthoxycarbonyloxy,1-ethylpropoxycarbonyloxy, hexyloxycarbonyloxy, are mentioned.

Preferable one is C₁₋₄ alkoxy carbonyloxy group. More preferable istert-buthoxycarbonyloxy. Preferable one is tert-butoxycarbonyl.

A “C₁₋₆ alkyl sulfonyl C₁₋₆ alkyl” group means a group in which “C₁₋₆alkyl sulfonyl” group of the above-mentioned definition is mono- ordi-substituted on the “C₁₋₆ alkyl” group of the above-mentioneddefinition. When the C₁₋₆ alkyl sulfonyl groups are di-substituted, eachC₁₋₆ alkyl sulfonyl group is the same or different. A preferable groupis a group which is mono-substituted by C₁₋₆ alkyl sulfonyl group.

As this group, for example, methylsulfonylmethyl and ethylsulfonylmethyl(namely, ethanesulfonylmethyl), propylsulfonylmethyl,isopropylsulfonylmethyl (namely, propane-2-sulfonylmethyl),n-butylsulfonylmethyl, isobutylsulfonylmethyl (namely,2-methylpropane-1-sulfonylmethyl), sec-butylsulfonylmethyl,tert-butylsulfonylmethyl (namely, 2-methyl-propane-2-sulfonylmethyl),pentylsulfonylmethyl, 1,1-dimethylpropylsulfonylmethyl,hexylsulfonylmethyl, 2,2-dimethylpropylsulfonylmethyl (namely,2,2-dimethylpropane-1-sulfonylmethyl), 1-ethylsulfonylethyl (namely,1-ethanesulfonylethyl), 1-isopropylsulfonylethyl (namely,1-(propane-2-sulfonyl)-ethyl), 2-ethylsulfonylethyl (namely,2-ethanesulfonylethyl), 2-isopropylsulfonylethyl (namely,2-(propane-2-sulfonyl)-ethyl), 2,3-bis-methanesulfonylpropyl,2,3-bis-methanesulfonyl-1-methylpropyl etc. are mentioned.

Preferable one is C₁₋₄ alkyl sulfonyl C₁₋₃ alkyl group. More preferableare ethanesulfonylmethyl and propane-2-sulfonylmethyl.

A “halo C₁₋₆ alkyl sulfonyl C₁₋₆ alkyl” group means a group in which“halo C₁₋₆ alkyl sulfonyl” group of the above-mentioned definition ismono- or di-substituted on the “C₁₋₆ alkyl” group of the above-mentioneddefinition. When the halo C₁₋₆ alkyl sulfonyl groups are di-substituted,each halo C₁₋₆ alkyl sulfonyl group is the same or different. Apreferable group is a group which is mono-substituted by halo C₁₋₆ alkylsulfonyl group.

As this group, for example 2-fluoroethanesulfonylmethyl,2-chloroethanesulfonylmethyl, 2-bromoethanesulfonylmethyl,3-fluoropropanesulfonylmethyl, 3-chloropropanesulfonylmethyl,4-fluorobutanesulfonylmethyl, 4-chlorobutanesulfonylmethyl,1,1-difluoroethanesulfonylmethyl, 1,1-difluoropropanesulfonylmethyl,1,1-difluoro-isobutanesulfonylmethyl, trifluoromethanesulfonylmethyl,2,2,2-trifluoroethanesulfonylmethyl,3,3,3-trifluoropropanesulfonylmethyl,4,4,4-trifluorobutanesulfonylmethyl, pentafluoroethanesulfonylmethyl,2,2,2-trifluoro-1-trifluoromethyl-ethanesulfonylmethyl,1-trifluoromethanesulfonylethyl,1-(2,2,2-trifluoroethanesulfonyl)-ethyl,1-(3,3,3-trifluoropropanesulfonyl)-ethyl,1-(4,4,4-trifluorobutanesulfonyl)-ethyl,1-(2,2,2-trifluoro-1-trifluoromethyl-ethanesulfonyl)-ethyl,2-trifluoromethanesulfonylethyl,2-(2,2,2-trifluoroethane-sulfonyl)-ethyl,2-(3,3,3-trifluoropropanesulfonyl)-ethyl,2-(4,4,4-trifluorobutanesulfonyl)-ethyl,2-(2,2,2-trifluoro-1-trifluoromethylethanesulfonyl)-ethyl,1-methyl-1-trifluoromethanesulfonylethyl,1-methyl-1-(2,2,2-trifluoroethanesulfonyl)-ethyl,1-methyl-1-(3,3,3-trifluoropropanesulfonyl)-ethyl,1-methyl-1-(4,4,4-trifluorobutanesulfonyl)-ethyl,1-methyl-1-(2,2,2-trifluoro-1-trifluoromethyl ethanesulfonyl)-ethyl,2,3-bis(2,2,2-trifluoroethanesulfonyl)propyl,1-methyl-2,3-bis(2,2,2-trifluoroethanesulfonyl)propyl, are mentioned.

Preferable one is halo C₁₋₄ alkyl sulfonyl C₁₋₃ alkyl group. Preferableone is 2,2,2-trifluoro ethanesulfonylmethyl.

A “C₁₋₆ alkyl sulfanyl C₁₋₆ alkoxy” group means a group in which “C₁₋₆alkyl sulfanyl” group of the above-mentioned definition is mono- ordi-substituted on the “C₁₋₆ alkoxy” group of the above-mentioneddefinition. When the C₁₋₆ alkyl sulfanyl groups are di-substituted, eachC₁₋₆ alkyl sulfanyl group is the same or different. A preferable groupis a group which is mono-substituted by a C₁₋₆ alkyl sulfanyl group.

xxxAs this group, for example, 2-methylsulfanylethoxy,2-ethylsulfanylethoxy, 2-propylsulfanylethoxy,2-isopropylsulfanylethoxy, 2-n-butylsulfanylethoxy,2-isobutylsulfanylethoxy, 2-sec-butyl sulfanylethoxy, 2-tert-butylsulfanylethoxy, 2-pentylsulfanylethoxy,2-(1,1-dimethylpropylsulfanyl)ethoxy,2-(2,2-dimethylpropylsulfanyl)ethoxy, 2-hexylsulfanylethoxy,3-methylsulfanylpropoxy, 3-ethylsulfanylpropoxy,3-propylsulfanylpropoxy, 3-isopropylsulfanylpropoxy,3-n-butylsulfanylpropoxy, 3-isobutylsulfanylpropoxy,3-sec-butylsulfanylpropoxy, 3-tert-butyl sulfanylpropoxy,3-pentylsulfanylpropoxy, 3-(1,1-dimethylpropylsulfanyl)propoxy,3-(2,2-dimethylpropylsulfanyl)propoxy, 3-hexylsulfanylpropoxy,2-methyl-3-methylsulfanylpropoxy, 2-methyl-3-isopropylsulfanylpropoxy,2-methyl-3-(2,2-dimethylpropylsulfanyl)-propoxy,2,3-bis-methylsulfanylpropoxy, 1-methyl-2,3-bis-methylsulfanylpropoxyare mentioned.

Preferable one is C₁₋₃ alkyl sulfanyl C₂₋₄ alkoxy. More preferable is3-methylsulfanylpropoxy.

A “C₁₋₆ alkyl sulfonyl C₁₋₆ alkoxy” group means a group in which the“C₁₋₆ alkylsulfonyl” group of the above-mentioned definition is mono- ordi-substituted on the “C₁₋₆ alkoxy” group of the above-mentioneddefinition. When the C₁₋₆ alkyl sulfonyl groups are di-substituted, eachC₁₋₆ alkyl sulfonyl group may be the same or different.

A preferable group is a group which is mono-substituted by a C₁₋₆ alkylsulfonyl group.

As this group, for example, 2-methylsulfonylethoxy,2-ethylsulfonylethoxy, 2-propylsulfonylethoxy,2-isopropylsulfonylethoxy, 2-n-butylsulfonylethoxy,2-isobutylsulfonylethoxy, 2-sec-butylsulfonylethoxy,2-tert-butylsulfonylethoxy, 2-pentylsulfonylethoxy,2-(1,1-dimethylpropylsulfonyl)ethoxy,2-(2,2-dimethylpropylsulfonyl)ethoxy, 2-hexylsulfonylethoxy,3-methylsulfonylpropoxy, 3-ethylsulfonylpropoxy,3-propylsulfonylpropoxy, 3-isopropylsulfonylpropoxy,3-n-butylsulfonylpropoxy, 3-isobutylsulfonylpropoxy,3-sec-butylsulfonylpropoxy, 3-tert-butylsulfonylpropoxy,3-pentylsulfonylpropoxy, 3-(1,1-dimethylpropylsulfonyl)propoxy,3-(2,2-dimethylpropylsulfonyl)propoxy, 3-hexylsulfonylpropoxy,2-methyl-3-methylsulfonylpropoxy, 2-methyl-3-isopropylsulfonylpropoxy,2-methyl-3-(2,2-dimethylpropylsulfonyl)-propoxy,2,3-bis-methylsulfonylpropoxy, 1-methyl-2,3-bis-methylsulfonylpropoxyare mentioned.

Preferable one is C₁₋₃ alkyl sulfonyl C₂₋₄ alkoxy. More preferable is3-methanesulfonylpropoxy.

A “halo C₁₋₆ alkylamino C₁₋₆ alkyl” group means a group in which anamino group, on which the “halo C₁₋₆ alkyl” group of the above-mentioneddefinition is mono- or di-substituted, is mono- or di-substituted on the“C₁₋₆ alkyl” group of the above-mentioned definition. A preferable groupis a group which is mono-substituted by an amino group on which the haloC₁₋₆ alkyl group is mono-substituted.

As this group, for example, 2-fluoroethylaminomethyl,2-chloroethylaminomethyl, 2-bromoethylaminomethyl,3-fluoropropylaminomethyl, 3-chloropropylaminomethyl,4-fluorobutylaminomethyl, 4-chlorobutylaminomethyl,1,1-difluoroethylaminomethyl, 1,1-difluoropropylaminomethyl,1,1-difluoro-2-methylpropylaminomethyl, 2,2,2-trifluoroethylaminomethyl,3,3,3-trifluoropropylaminomethyl, 4,4,4-trifluorobutylaminomethyl,2,2,3,3,3-pentafluoropropylaminomethyl,1-(2,2,2-trifluoroethylamino)-ethyl,2-(2,2,2-trifluoroethylamino)-ethyl,1-methyl-1-(2,2,2-trifluoroethylamino)-ethyl, bis-(2,2,2-trifluoroethyl)aminomethyl, are mentioned.

Preferable one is halo C₁₋₃ alkylamino C₁₋₃ alkyl group. More preferableis 2,2,2-trifluoroethyl aminomethyl.

As “C₃₋₈ cycloalkyloxy” group, cyclopropyloxy, cyclobutoxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, arementioned, for example.

Preferable one is C₃₋₆ cycloalkyloxy group. More preferable iscyclopentyloxy and cyclobutoxy.

A “saturated heterocyclo oxy” group means a group in which a chemicallyacceptable carbon atom in the “saturated heterocycle” group of theabove-mentioned definition, and an oxygen atom are combined.

As this group, for example, oxetan-3-yloxy, tetrahydrofuran-3-yloxy,(R)-tetrahydrofuran-3-yloxy, (S)-tetrahydrofuran-3-yloxy,tetrahydropyran-3-yloxy, (R)-tetrahydropyran-3-yloxy,(S)-tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy,tetrahydrothiopyran-4-yloxy, are mentioned.

Preferable one is oxetan-3-yloxy.

A “saturated heterocyclo oxy C₁₋₆ alkyl” group means a group in whichthe “saturated heterocyclo oxy” group of the above-mentioned definitionis mono- or di-substituted on the “C₁₋₆ alkyl” group of theabove-mentioned definition. When the saturated heterocyclo oxy groupsare di-substituted, each saturated heterocyclo oxy group is the same ordifferent.

As this group, for example, oxetan-3-yloxymethyl,tetrahydrofuran-3-yloxymethyl, (R)-tetrahydrofuran-3-yloxymethyl,(S)-tetrahydrofuran-3-yloxymethyl, tetrahydropyran-3-yloxymethyl,(R)-tetrahydropyran-3-yloxymethyl, (S)-tetrahydropyran-3-yloxymethyl,tetrahydropyran-4-yloxymethyl, pyrrolidin-3-yloxymethyl,piperidine-3-yloxymethyl, piperidin-4-yloxymethyl,tetrahydrothiopyran-4-yloxymethyl, 1-(oxetan-3-yloxy)-ethyl,1-(tetrahydropyran-4-yloxy)-ethyl, 2-(oxetan-3-yloxy)-ethyl,2-(tetrahydropyran-4-yloxy)-ethyl, etc. are mentioned.

Preferable one is saturated heterocyclo oxy C₁₋₃ alkyl group. Morepreferable are oxetan-3-yloxymethyl, (R)-tetrahydrofuran-3-yloxymethyl,(S)-tetrahydrofuran-3-yloxymethyl, (R)-tetrahydropyran-3-yloxymethyl,(S)-tetrahydropyran-3-yloxymethyl, and tetrahydropyran-4-yloxymethyl.

A “saturated heterocyclo C₁₋₆ alkoxy” group means a group in which the“saturated heterocyclo” group of the above-mentioned definition is mono-or di-substituted on the “C₁₋₆ alkoxy” group of the above-mentioneddefinition. When the saturated heterocycle groups are di-substituted,each saturated heterocycle group is the same or different.

As this group, for example, (3-pyrrolidinyl)methoxy (namely,pyrrolidin-3-ylmethoxy), (4-piperidinyl)methoxy, oxetan-3-ylmethoxy,(4-tetrahydropyranyl)methoxy, 2-(1-pyrrolidinyl)ethoxy,2-(1-piperidinyl)ethoxy, 2-(4-morpholinyl)ethoxy, 2-(4-thiomorpholinyl)ethoxy, 2-(1-piperazinyl)ethoxy, 2-oxetan-3-ylethoxy,2-(4-tetrahydropyranyl) ethoxy, 2-(4-tetrahydropyranyl)propoxy arementioned.

Preferable one is saturated heterocyclo C₁₋₃ alkoxy group. Morepreferable is oxetan-3-ylmethoxy.

A “C₆₋₁₀ aryl C₁₋₆ alkoxy C₁₋₆ alkoxy” group means a group in which the“C₆₋₁₀ aryl C₁₋₆ alkoxy” group of the above-mentioned definition ismono- or di-substituted on the “C₁₋₆ alkoxy” group of theabove-mentioned definition. When the C₆₋₁₀ aryl C₁₋₆ alkoxy group isdi-substituted, each C₆₋₁₀ aryl C₁₋₆ alkoxy group is the same ordifferent.

As this group, for example, 2-benzyloxyethoxy, 2-naphthlmethyloxyethoxy,2-(1-phenylethyloxy)-ethoxy, 2-(2-phenylethyloxy)-ethoxy,2-(2-naphthylethyloxy)-ethoxy, 2-(3,3-diphenylpropoxy)-ethoxy,3-benzyloxypropoxy, 3-naphthlmethyloxypropoxy,3-(1-phenylethyloxy)-propoxy, 3-(2-phenylethyloxy)-propoxy,3-(2-naphthylethyloxy)-propoxy, 3-(3,3-diphenylpropoxy)-propoxy,3-benzyloxy-2-methylpropoxy, 2,3-bis-benzyloxypropoxy are mentioned.

Preferable one is C₆₋₁₀ aryl C₁₋₃ alkyl C₁₋₃ alkoxy group. Morepreferable is 2-benzyloxyethoxy.

The case as used in “—(CH₂)_(m)—X^(a)—(C═O)—” where X^(a) is a “bond”means “—(CH₂)_(m)—(C═O)—”.

In the general Formula [I], R³ is optionally substituted on carbon atomsin heterocycle within the chemically acceptable range, and is notsubstituted on heteroatoms.

In the general formula [Ib], R^(3a) and R^(3b) on heterocycles denotedby seven kinds of formulae for the ring Cy^(a) are optionallysubstituted on carbon atoms in the heterocycle within the chemicallyacceptable range, and are not substituted on heteroatoms.

In the case that the ring Cy^(a) is of the Formula:

the following Formula:

is exemplified for the compound represented by “when two R^(3b) areattached to the same carbon, they optionally form C₃₋₆ cycloalkyl grouptogether with the carbon to which they are attached”.

In the case that the ring Cy^(a) is of the Formula:

and R^(3b) is C₁₋₆ alkyl, the following Formula:

is exemplified for the compound represented by “R^(3b) optionally formC₃₋₆ cycloalkyl group together with the carbon to which it is attachedand the carbon adjacent thereto”.

The preferable embodiments about each group of the compound (it is alsohenceforth called a “compound of the present invention”.) represented bythe general formula [I] are explained below.

The preferable embodiment of the ring Cy is C₆₋₁₀ aryl. The preferableexamples of the ring Cy are phenyl, cyclopentyl, cyclohexyl,cycloheptyl, 1-cyclohexenyl. A more preferable ring Cy is phenyl.

The preferable example of n1 is 1, 2, 3 or 4. More preferable n1 is 1.

The preferable embodiment of R¹ is

(1) a halogen atom,(2) hydroxy,(3) carboxy,(4) a C₁₋₃ alkyl group,(5) a C₁₋₄ alkoxy group,(6) a C₃₋₆ cycloalkyl group,(7) a halo C₁₋₄ alkyl group,(8) a hydroxy C₁₋₄ alkyl group,(9) a C₁₋₄ alkoxy C₁₋₃ alkyl group,(10) a halo C₁₋₄ alkoxy group or(11) a carboxy C₁₋₄ alkoxy group,provided, when n1 is 2, 3 or 4, R¹ each is the same or different.

Another preferable embodiment of R¹ is

(1) a halogen atom,(2) a C₁₋₆ alkyl group,(3) a C₁₋₆ alkoxy group,(4) a halo C₁₋₆ alkyl group,(5) a C₁₋₆ alkoxy C₁₋₆ alkyl group or(6) a halo C₁₋₆ alkoxy group,provided, when n1 is 2, 3 or 4, R¹ each is the same or different.

The preferable example of R¹ is fluoro, chloro, hydroxy, carboxy,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl,1,1-dimethylpropyl, ethoxy, cyclopropyl, trifluoromethyl,1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluoro-2-methylpropyl,hydroxymethyl, 1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy orcarboxymethoxy.

The preferable embodiment of R² is

(1) a C₁₋₆ alkyl group,(2) a C₃₋₆ cycloalkyl C₁₋₃ alkyl group,(3) a C₆₋₁₀ aryl C₁₋₃ alkyl group,(4) a saturated heterocyclo C₁₋₃ alkyl group (the saturated heterocycleis of 5-membered to 6-membered saturated heterocycle having 1 to 2heteroatoms selected from nitrogen, oxygen, and sulfur),(5) a C₃₋₇ cycloalkyl group,(6) a halo C₁₋₄ alkyl group (the halos are 1 to 3 fluorine atoms),(7) a C₁₋₄ alkoxy C₁₋₃ alkyl group,(8) a halo C₃₋₈ cycloalkyl group (the halos are 1 to 3 fluorine atoms),(9) a phenyl group (the phenyl group is optionally substituted by the 1to 4 substituents selected from

-   -   (a) a halogen atom,    -   (b) a C₁₋₃ alkyl group,    -   (c) a C₁₋₃ alkoxy group and    -   (d) a carboxy C₁₋₃ alkoxy group), or        (10) a saturated heterocycle group (the saturated heterocycle is        of 5-membered to 6-membered saturated heterocycle having 1 to 2        heteroatoms selected from nitrogen, oxygen, and sulfur, and is        optionally substituted by 1 to 4 C₁₋₃ alkyl groups).

Another preferable embodiment of R² is a C₆₋₁₀ aryl group (the C₆₋₁₀aryl group is optionally substituted by the 1 to 4 substituents selectedfrom

(a) a halogen atom,(b) a C₁₋₆ alkyl group,(c) a C₁₋₆ alkoxy group, and(d) a carboxy C₁₋₆ alkoxy group).

The preferable examples of R² are ethyl, propyl, isopropyl,2-methylpropyl, tert-butyl, 3-methylbutyl, 3,3-dimethylbutyl, hexyl,cyclohexylmethyl, cyclohexylethyl, benzyl, 2-phenylethyl,4-tetrahydropyranylmethyl, 2-(4-tetrahydropyranyl)ethyl,2-(1-pyrrolidinyl)ethyl, cyclopentyl, cyclohexyl, cycloheptyl,trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,4,4-difluorocyclohexyl, 2-isopropoxyethyl, 2-cyclopentylethyl, phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl,2-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-methyl-4-fluorophenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-carboxymethoxyphenyl, 4-tetrahydropyranyl and 2,6-dimethyl-4-tetrahydropyranyl.

More preferable R² is phenyl group.

The preferable example of n2 is 0, 1 or 2.

More preferable n2 is 0 or 1.

The preferable example of m is 0, 1 or 2.

The preferable example of R³ is methyl, ethyl or 2-hydroxyethyl.

The preferable example of X^(a) is a bond, NH or N-methyl.

More preferable X^(a) is a bond.

The preferable example of X^(b) is NH.

The preferable example of R⁴ is a hydrogen atom or methyl.

The preferable embodiments of each group of the compound (it is alsohenceforth called a “compound of the present invention”.) represented bythe general formula [Ib] are explained below.

The preferable embodiment of the ring Cy is C₆₋₁₀ aryl. The preferableexamples of the ring Cy are phenyl, cyclopentyl, cyclohexyl,cycloheptyl, 1-cyclohexenyl. A more preferable ring Cy is phenyl.

The preferable example of n1 is 1, 2, 3 or 4. More preferable n1 is 1 or2.

The preferable embodiment of R^(1a) is

(1) a halogen atom,(2) a C₁₋₆ alkyl group,(3) a C₁₋₆ alkoxy group,(4) a C₃₋₆ cycloalkyl group,(5) a halo C₁₋₆ alkyl group,(6) a hydroxy C₁₋₆ alkyl group,(7) a C₁₋₆ alkoxy C₁₋₆ alkyl group,(8) a halo C₁₋₆ alkoxy C₁₋₆ alkyl group,(9) a C₁₋₆ (alkylsulfonyl C₁₋₆ alkyl group,(10) a halo C₁₋₆ alkylamino C₁₋₆ alkyl group,(11) a halo C₁₋₆ alkoxy group,(12) a carboxy C₁₋₆ alkoxy group,(13) a saturated heterocyclo C₁₋₆ alkyl group (the saturated heterocycleis of 4-membered to 6-membered saturated heterocycle having 1 to 2heteroatoms selected from nitrogen, oxygen, and sulfur) or(14) a saturated heterocyclo oxy C₁₋₆ alkyl group (the saturatedheterocycle is of 4-membered to 6-membered saturated heterocycle having1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur),provided when n1 is 2, 3 or 4, R^(1a) each is the same or different.

Another preferable embodiment of R^(1a) is

(1) a halogen atom,(2) a C₁₋₆ alkyl group,(3) a C₁₋₆ alkoxy group,(4) a halo C₁₋₆ alkyl group,(5) a C₁₋₆ alkoxy C₁₋₆ alkyl group,(6) a halo C₁₋₆ alkoxy group or(7) a halo C₁₋₆ alkoxy C₁₋₆ alkyl group,provided, when n1 is 2, 3 or 4, R^(1a) each is the same or different.

Another preferable embodiment of R^(1a) is

(1) a halogen atom,(2) a C₁₋₆ alkyl group,(3) a halo C₁₋₆ alkoxy group or(4) a halo C₁₋₆ alkoxy C₁₋₆ alkyl group,provided, when n1 is 2, 3 or 4, R^(1a) each is the same or different.

Preferable examples of R^(1a) are chloro, fluoro, hydroxy, carboxy,methyl, ethyl, n-butyl, tert-butyl, propyl, isopropyl,1,1-difluoropropyl, 1,1-dimethylpropyl, 2-methylpropyl,3,3-dimethylbut-1-enyl, 3,3-dimethyl but-1-ynyl ethoxy, propoxy,1,1-dimethylpropoxy, 2,2-dimethylpropoxy, isopropoxy, butoxy, isobutoxy,3,3-dimethylbutoxy, tert-butoxy, 3-methylbutoxy, cyclopropyl,trifluoromethyl, 1,1-difluoroethyl, 1,1-difluoro-2-methylpropyl,1,1-difluoropropyl, hydroxymethyl, 1-hydroxy-1-methylethyl,1-hydroxy-2,2-dimethylpropyl, 1-hydroxy-2,2-dimethylbutyl,methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl,isobutoxymethyl, tert-butoxymethyl, (R)-sec-butoxymethyl,(S)-sec-butoxymethyl, 1-ethylpropoxymethyl, (R)-1-propoxyethyl,(S)-1-propoxyethyl, 1-ethoxy-1-methylethyl, 1-methoxy-1-methylethyl,2,2-dimethylpropoxymethyl, 2-methoxy-1,1-dimethylethyl,1-methyl-1-propoxy-ethyl, trifluoromethoxymethyl,2,2,2-trifluoroethoxymethyl, 3,3,3-trifluoro propoxymethyl,(R)-2,2,2-trifluoro-1-methylethoxymethyl,(S)-2,2,2-trifluoro-1-methylethoxymethyl,2,2,2-trifluoro-1,1-dimethyl-ethoxymethyl,2,2,2-trifluoro-1-trifluoromethylethoxymethyl,2,2,2-trifluoro-1-methyl-1-trifluoromethyl-ethoxymethyl,ethanesulfonylmethyl, propane-2-sulfonylmethyl, 2,2,2-trifluoroethanesulfonylmethyl, 2,2,2-trifluoroethyl aminomethyl,cyclopropylethynyl, trifluoromethoxy, 2,2,2-trifluoroethoxy,3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, carboxymethoxy,isobutylsulfanyl, propane-2-sulfonyl, 2-methylpropane-1-sulfonyl,2-methyl-propane-2-sulfonyl, 2,2-dimethylpropane-1-sulfonyl,2,2,2-trifluoroethanesulfonyl, 3,3,3-trifluoropropanesulfonyl,2,2-dimethylbutyryl, 2,2-dimethylpropionyl, tert-butoxycarbonyl,propylcarbamoyl, isopropylcarbamoyl, methylpropylcarbamoyl,2,2,2-trifluoroethylcarbamoyl, isopropylmethylcarbamoyl,pyrrolidine-1-ylmethyl, (R)-tetrahydrofuran-3-yloxymethyl,(S)-tetrahydrofuran-3-yloxymethyl, (R)-tetrahydropyran-3-yloxymethyl,(S)-tetrahydropyran-3-yloxymethyl, oxetane-3-yloxymethyl andtetrahydropyran-4-yloxymethyl.

More preferable examples of R^(1a) are n-butyl, trifluoromethoxy,2,2,2-trifluoroethoxymethyl,2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl,(R)-2,2,2-trifluoro-1-methylethoxymethyl,(S)-2,2,2-trifluoro-1-methylethoxymethyl and2,2,2-trifluoro-1,1-dimethylethoxymethyl.

A preferable embodiment of R^(2a) is

(1) a C₆₋₁₀ aryl group (the C₆₋₁₀ aryl group is optionally substitutedby 1 to 4 substituents selected from

-   -   (a) a halogen atom,    -   (b) hydroxy,    -   (c) a C₁₋₆ alkyl group,    -   (d) a C₂₋₈ alkenyl group,    -   (e) a C₂₋₆ alkynyl group,    -   (f) a C₁₋₆ alkoxy group,    -   (g) a halo C₁₋₆ alkyl group,    -   (h) a C₁₋₆ alkoxy C₁₋₆ alkyl group,    -   (i) a halo C₁₋₆ alkoxy group,    -   (j) a hydroxy C₁₋₆ alkoxy group,    -   (k) a C₁₋₆ alkoxy C₁₋₆ alkoxy group,    -   (l) a carboxy C₁₋₆ alkoxy group,    -   (m) a C₆₋₁₀ aryl C₁₋₆ alkoxy group,    -   (n) a C₁₋₆ alkylsulfanyl C₁₋₆ alkoxy group,    -   (o) a C₁₋₆ alkyl sulfonyl C₁₋₆ alkoxy group,    -   (p) a C₆₋₁₀ aryl C₁₋₆ alkoxy C₁₋₆ alkoxy group,    -   (q) a saturated heterocyclo C₁₋₆ alkoxy group (the saturated        heterocycle is 4-membered to 6-membered saturated heterocycle        having 1 to 2 heteroatoms selected from nitrogen, oxygen, and        sulfur and is optionally substituted by 1 to 2 C₁₋₆ alkyl        groups),    -   (r) a saturated heterocyclo oxy group (the saturated heterocycle        is 4-membered to 6-membered saturated heterocycle having 1 to 2        heteroatoms selected from nitrogen, oxygen and sulfur,    -   (s) a C₃₋₈ cycloalkyloxy group,    -   (t) a C₁₋₆ alkoxycarbonyloxy group and    -   (u) a C₁₋₆ alkylsulfonyl group), or        (2) A saturated heterocycle group (the saturated heterocycle is        4-membered to 6-membered saturated heterocycle having 1 to 2        heteroatoms selected from nitrogen, oxygen and sulfur, and is        optionally substituted by 1 to 4 C₁₋₆ alkyl groups).

Preferable examples of R^(2a) are ethyl, propyl, isopropyl,2-methylpropyl, tert-butyl, 3-methylbutyl, 3,3-dimethylbutyl, hexyl,cyclohexylmethyl, cyclohexylethyl, benzyl, 2-cyclopentylethyl,2-phenylethyl, 4-tetrahydropyranylmethyl, 2-(4-tetrahydropyranyl)ethyl,2-(1-pyrrolidinyl)ethyl, cyclopentyl, cyclohexyl, cycloheptyl,trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,2-isopropoxyethyl, 4,4-difluorocyclohexyl, phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl,3-fluoro-4-chlorophenyl, 5-chloro-2-fluorophenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,3,5-dimethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl,2,6-dimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl,3-propylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl,3-isobutylphenyl, 3-(3,3-dimethyl-butyl)phenyl, 3-tert-buthylphenyl,3-(2-methylpropenyl)-phenyl, ((E)-3-propenyl)-phenyl,3-(3,3-dimethylbut-1-ynyl)-phenyl, 2-methoxypheny, 3-methoxypheny,4-methoxypheny, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl,3-propoxyphenyl, 4-propoxyphenyl, 2-isopropoxyphenyl,3-isopropoxyphenyl, 4-isopropoxyphenyl, 3-isobutoxyphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-methoxymethylphenyl,3-isopropoxymethyl-phenyl, 3-trifluoromethoxy-phenyl,4-trifluoromethoxy-phenyl, 4-(2,2,2-trifluoro-ethoxy)-phenyl,4-(3,3,3-trifluoro-propoxy)-phenyl, 3-(2,2,2-trifluoro-ethoxy)-phenyl,3-(2-hydroxyethoxy)-phenyl, 3-(2-methoxyethoxy)-phenyl,3-carboxymethoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl,3-(3-methylsulfanylpropoxy)-phenyl, 3-(3-methanesulfonylpropoxy)-phenyl,3-(2-benzyloxyethoxy)-phenyl, 3-(3-methyloxetan-3-ylmethoxy)-phenyl,3-(oxetan-3-yloxy)-phenyl, 3-cyclopentyloxyphenyl, 3-cyclobutoxyphenyl,3-tert-buthoxycarbonyloxyphenyl, 3-methanesulfonylphenyl,4-tetrahydropyranyl, 2,6-dimethyl-4-tetrahydropyranyl,4-fluoro-2-methyl-phenyl, 4-fluoro-3-(2-hydroxyethoxy)-phenyl,4-fluoro-3-(2-methoxyethoxy)-phenyl,2-fluoro-3-(2-methoxyethoxy)-phenyl,2-fluoro-5-(2-methoxyethoxy)-phenyl,2-fluoro-3-(2-methoxyethoxy)-phenyl, 2-fluoro-3-methoxy-phenyl,4-fluoro-3-methoxy-phenyl, 2-fluoro-5-methoxy-phenyl,3-fluoro-5-methoxy-phenyl, 3-ethoxy-4-fluoro-phenyl,3-ethoxy-2-fluoro-phenyl, 5-ethoxy-2-fluoro-phenyl,3-ethoxy-5-fluoro-phenyl, 4-fluoro-3-isopropoxyphenyl,2-fluoro-5-isopropoxyphenyl, 3-fluoro-5-isopropoxyphenyl,2-fluoro-3-isopropoxyphenyl, and 4-fluoro-3-propoxy-phenyl.

More preferable examples of R^(2a) are phenyl, 4-chlorophenyl,2-fluorophenyl, 3-fluorophenyl and 4-fluorophenyl.

A preferable example of n2 is 0, 1 or 2.

More preferable n2 is 0 or 1.

A preferable example of m2 is 1 or 2, and

a preferable example of m3 is 1 or 2,provided, the sum of m2 and m3 is 3 or 4.

A preferable example of m4 is 1 or 2, and

a preferable example of m5 is 0, 1 or 2,provided, the sum of m4 and m5 is 2, 3 or 4.

A preferable example of m6 is 0 or 1, and

a preferable m7 is 0, 1 or 2,provided, the sum of m6 and m7 is 1 or 2.

A preferable example of m8 is 1.

A preferable example of m9 is 1.

Preferable examples of the ring Cy^(a) are

Other preferable examples of the ring Cy^(a) are

More preferable examples of the ring Cy^(a) are

A preferable example of R^(3a) is hydroxy, methyl, ethyl or2-hydroxyethyl.

A more preferable example of R^(3a) is methyl.

A preferable example of R^(3b) is hydroxy, methyl, ethyl,2-hydroxyethyl, cyclopropyl group which is formed by combining twomethyl groups attached on the same carbon with the carbon to which theyare attached, or cyclopropyl group which is formed by joining two methylgroups together with the adjacent carbons to which they are attached.

A more preferable example of R^(3b) is methyl.

A preferable example of R^(4b) is hydrogen atom, methyl, ethyl, propyl,isopropyl, carboxymethyl, 2,2,2-trifluoroethyl or 2-methoxyethyl.

A more preferable example of R^(4b) is hydrogen atom.

A certain preferable embodiment of the compound of the present inventionis a compound in general formula [I] wherein the ring Cy is phenyl, n1is 1, 2, 3 or 4 and X^(b) is NH, and the compound is represented by thegeneral formula [II]:

wherein n1′ is 0, 1, 2 or 3, and each of other symbols is the same asthose defined above.

Another preferable embodiment of the compound of the present inventionis a compound in general formula [I] wherein the ring Cy is phenyl, n1is 1, 2, 3 or 4, n2 is 0, m is 1, X^(a) is a bond and X^(b) is NH, andthe compound is represented by the general formula [III]:

wherein n1′ is 0, 1, 2 or 3, and each of other symbols is the same asthose defined above.

Another preferable embodiment of the compound of the present inventionis a compound in general formula [I] wherein the ring Cy is phenyl, n1is 1, 2, 3 or 4, n2 is 1, m is 1, X^(a) is a bond and X^(b) is NH, andthe compound is represented by the general formula [IV]:

wherein n1′ is 0, 1, 2 or 3, and each of other symbols is the same asthose defined above.

Another preferable embodiment of the compound of the present inventionis a compound in general formula [I] wherein the ring Cy is phenyl, n1is 1, 2, 3 or 4, n2 is 0, m is 2, X^(a) is a bond and X^(b) is NH, andthe compound is represented by the general formula [V]:

wherein n1′ is 0, 1, 2 or 3, and each of other symbols is the same asthose defined above.

A certain preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [VI]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove, and the compound is that in the general Formula [Ib], wherein thering Cy is phenyl and the ring Cy^(a) is represented by the Formula:

Another preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [VII]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove, and the compound is that in the general Formula [Ib], wherein thering Cy is phenyl and the ring Cy^(a) is represented by the Formula:

Another preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [VIII]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove, and the compound is that in the general Formula [Ib], wherein thering Cy is phenyl and the ring Cy^(a) is represented by the Formula:

Another preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [IX]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove, andthe compound is that in the general Formula [Ib], wherein the ring Cy isphenyl and the ring Cy^(a) is represented by the Formula:

Another preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [X]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove, and the compound is that in the general Formula [Ib], wherein thering Cy is phenyl and the ring Cy^(a) is represented by the Formula:

Another preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [XI]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove, and the compound is that in the general Formula [Ib], wherein thering Cy is phenyl and the ring Cy^(a) is represented by the Formula:

Another preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [XII]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove, andthe compound is that in the general Formula [Ib], wherein the ring Cy isphenyl and the ring Cy^(a) is represented by the Formula:

Another preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [XIII]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove, andthe compound is that in the general Formula [Ib], wherein the ring Cy isphenyl and the ring Cy^(a) is represented by the Formula:

Another preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [XIV]:

-   -   wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as        defined above, and        the compound is that in the general Formula [Ib], wherein the        ring Cy is phenyl and the ring Cy^(a) is represented by the        Formula:

A certain preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [XV]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove.

A certain preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [XVI]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove.

Another preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [XVII]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove.

A certain preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [XVIII]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove.

Another preferable embodiment of the compound of the present inventionis a compound represented by the general Formula [XIX]:

wherein, n1′ is 0, 1, 2 or 3, and other symbols are the same as definedabove.

A “pharmaceutically acceptable salt” of a compound of the presentinvention may be any nonpoisonous salt of a compound of the presentinvention and include any kind of salts, for example, a salt with aninorganic acid, a salt with an organic acid, a salt with an inorganicbase, a salt with an organic base and a salt with amino acid.

As the salt with an inorganic acid, salt with hydrochloric acid, nitricacid, sulfuric acid, phosphoric acid, hydrobromic acid are included, forexample.

As the salt with an organic acid, for example, salt with oxalic acid,maleic acid, citric acid, fumaric acid, lactic acid, malic acid,succinic acid, tartaric acid, acetic acid, trifluoroacetic acid,gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acidand p-toluenesulfonic acid are included.

As the salt with an inorganic base, for example, sodium salt, potassiumsalt, calcium salt, magnesium salt and ammonium salt are included.

As the salt with an organic base, for example, salts with methylamine,diethylamine, trimethylamine, triethylamine, ethanolamine,diethanolamine, triethanolamine, ethylenediamine, tris (hydroxymethyl)methylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, guanidine,pyridine, picoline, choline, cinchonine and meglumine are included.

As the salt with amino acid, for example, salts with lysine, arginine,aspartic acid and glutamic acid are included.

In accordance with known methods, each salt may be obtained by reactinga compound of the present invention with an inorganic base, an organicbase, an inorganic acid, an organic acid or amino acid.

Various “isomers” exist in the compound of the present invention. Forexample, E isomer and Z isomer exist as geometrical isomers. Whenasymmetric carbon atoms exist, the enantiomer and the diastereoisomer asstereoisomers based on these in compounds of the present inventionexist. When axial asymmetries exist, the stereoisomers based on theseexist. By a case, a compound of the present invention may exist intautomer. Therefore, these all isomers and mixtures thereof are includedin the scope of the present invention.

The compounds represented by the general formulae [I] and [Ib] orpharmaceutically acceptable salts thereof may be in a form of “solvate”thereof. The “solvate” means the compounds represented by the generalformulae [I] and [Ib] or pharmaceutically acceptable salts thereof towhich is coordinated by a solvent molecules. The solvate which ispharmaceutically acceptable is preferred. The solvate includes, forexample, hydrate, ethanolate, dimethyl sulfoxide solvate of thecompounds represented by the general formulae [I] and [Ib] orpharmaceutically acceptable salts thereof. Specifically, hemihydrate,monohydrate, dihydrate or mono ethanolate of the compound represented bygeneral formulae [I] and [Ib], or monohydrate of sodium salt of thecompound represented by general formulae [I] and [Ib], or 2/3-ethanolateof dihydrochloride of them is mentioned. The solvate may be obtained inaccordance with known methods.

A compound of the present invention may be labeled with isotopes (forexample, ²H, ³H, ¹⁴C, ³⁵S).

As a compound or a pharmaceutically acceptable salt thereof in thepresent invention, a compound or a pharmaceutically acceptable saltthereof in the present invention purified substantially is preferred. Acompound or a pharmaceutically acceptable salt thereof in the presentinvention over 80% or more of purities is more preferable.

In the present invention, prodrugs of the compounds represented by thegeneral formulae [I] and [Ib] can also serve as a useful medicine. The“prodrug” means a derivative of the compound of the present inventionwhich has a chemically or metabolically decomposable group, and uponadministered to the living body, the derivative restores to the originalcompound and exerts the original drug action after decomposition by, forexample, hydrolysis, solvolysis or decomposition under physiologicalcondition. In the derivatives, a complex and a salt which are not formedby a covalent bond are also included. The prodrug is used for theabsorption improvement in oral administration, or for targeting to atargeted position, for example. As a modification site to form aprodrug, functional groups with high reactivity such as hydroxy group,carboxy group, and amino group in the compound of the present inventionare included.

A modifying group for hydroxy group includes, specifically, acetylgroup, propionyl group, isobutyryl group, pivaloyl group, palmitoylgroup, benzoyl group, 4-methylbenzoyl group, dimethylcarbamoyl group,dimethylaminomethylcarbonyl group, sulfo group, alanyl group, fumarylgroup, etc. 3-Carboxybenzoyl group and 2-carboxyethylcarbonyl groupwhich are in the form of sodium-salt are also included.

A modifying group for carboxy group includes, specifically, methylgroup, ethyl group, propyl group, isopropyl group, butyl group,iso-butyl group, tert-butyl group, pivaloyloxymethyl group,carboxymethyl group, dimethylaminomethyl group, 1-(acetyloxy)ethylgroup, 1-(ethoxycarbonyloxy)ethyl group,1-(isopropyloxycarbonyloxy)ethyl group,1-(cyclohexyloxycarbonyloxy)ethyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, benzyl group, phenylgroup, o-tolyl group, morpholinoethyl group, N,N-diethylcarbamoylmethylgroup, phthalidyl group, etc.

A modifying group for amino group includes, specifically, tert-butylgroup, docosanoyl group, pivaloylmethyloxy group, alanyl group,hexylcarbamoyl group, pentylcarbamoyl group,3-methylthio-1-(acetylamino)propylcarbonyl group,1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, tetrahydrofuranylgroup and pyrrolidylmethyl group, etc.

Since a compound or a pharmaceutically acceptable salt thereof in thepresent invention has SGLT1 inhibitory activity, it is useful for thetreatment and/or prevention of various diseases or conditions of whichmay be expected to be improved by regulation of SGLT1 activity, forexample, diabetes, obesity, diabetic complication (for example,retinopathy, nephropathy and neuropathy which are known asmicroangiopathy, as well as cerebrovascular disease, ischemic heartdisease and membrum-inferius arteriosclerosis obliterans which are knownas macroangiopathy), hypertrophic cardiomyopathy, ischemic heartdisease, cancer and constipation. Diabetes is type II diabetes mellituspreferably.

“Inhibition of SGLT1” means inhibiting the function of SGLT1, anddisappearing or decreasing the activity, and, for example, meansinhibiting the function of SGLT1 based on the conditions of the examplesof examinations mentioned below. A preferable “inhibition of SGLT1” is“inhibition of human SGLT1”. A preferable “SGLT1 inhibitor” is “humanSGLT1 inhibitor”.

“Treatment” means alleviating or healing symptoms or disease, and/or itsaccompanying symptoms.

“Prevention” means a method of delaying or preventing the onset ofsymptoms or disease, and/or its accompanying symptoms, a method ofkeeping a patient from acquiring symptoms or disease, or a method ofreducing a risk of a patient acquiring symptoms or disease.

The pharmaceutical composition of the present invention is manufacturedby suitably mixing a compound or a pharmaceutically acceptable saltsthereof in the present invention with at least one or more sorts ofpharmaceutically acceptable carriers etc. in suitable amounts inaccordance with known methods in the technical field of medicinalpreparation. Content amounts of a compound or a pharmaceuticallyacceptable salt thereof in the present invention in the pharmaceuticalcomposition change depending on dosage forms, dose, etc., but are 0.1 to100% of the weight to the whole pharmaceutical composition, for example.

A “pharmaceutical compositions” include oral preparations such astablets, capsules, granules, powders, trochiscus, syrups, emulsion, andsuspension, and parenteral preparations such as external preparations,suppositories, injections, ophthalmic solutions, intranasal agents, andpulmonary agents.

A “pharmaceutically acceptable carriers” includes various conventionalorganic or inorganic carrier substances, for example, substances insolid preparations such as excipients, disintegrators, binders, glidantsand lubricants, and substances in liquid preparations such as solvents,solubilizing agents, suspending agents, isotonizing agents, buffers andsoothing agents. Additives such as preservatives, antioxidants,colorants, and edulcorants, are used if needed.

The “excipients” includes, for example, lactose, white soft sugar,D-mannitol, D-sorbitol, corn starch, dextrin, microcrystallinecellulose, crystalline cellulose, carmellose, carmellose calcium,carboxy-methyl-starch sodium, low substituted hydroxypropylcellulose andacacia.

The “disintegrators” include for example, carmellose, carmellosecalcium, carmellose sodium, carboxy-methyl-starch sodium,cross-carmellose sodium, crospovidone, low substitutedhydroxypropylcellulose, hydroxypropylmethyl cellulose and crystallinecellulose.

The “binders” include, for example, hydroxypropylcellulose,hydroxypropylmethyl cellulose, povidone, crystalline cellulose, whitesoft sugar, dextrin, starch, gelatin, carmellose sodium and acacia.

The “glidants” include, for example, light anhydrous silicic acid andmagnesium stearate.

The “lubricants” include, for example, magnesium stearate, calciumstearate and talc.

The “solvents” include, for example, purified water, ethanol, propyleneglycol, macrogol, sesame oil, corn oil and olive oil.

The “solubilizing agents” include, for example, propylene glycol,D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonateand sodium citrate.

The “suspending agents” include, for example, benzalkonium chloride,carmellose, hydroxypropylcellulose, propylene glycol, povidone,methylcellulose and glyceryl monostearate.

The “isotonizing agents” include, for example, glucose, D-sorbitol,sodium chloride and D-mannitol.

The “buffers” include, for example, disodium hydrogen phosphate, sodiumacetate, sodium carbonate and sodium citrate.

The “soothing agents” include, for example, benzyl alcohol.

The “preservatives” include, for example, ethyl parahydroxybenzoate,chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.

The “antioxidants” include, for example, sodium sulfite and ascorbicacid.

The “colorants” include, for example, food colors (for example, Food RedNo. 2 or No. 3, Food Yellow No. 4, or No. 5) and beta-carotene.

The “edulcorant” include, for example, saccharin sodium, glycyrrhizinatedipotassium and aspartame.

The pharmaceutical composition of the present invention can beadministrated to mammals other than human (for example, mice, rats,hamsters, guinea pigs, rabbits, cats, dogs, pig, cows, horses, sheeps,monkeys) and to human, in oral or parenteral (for example, topical,rectum, intravenous administration) in a therapeutically effectiveamount. Although the “therapeutically effective amount” changesdepending on patients, disease, symptoms, dosage forms, routes ofadministration, for example, the dose in the case of administeringorally to the adult patient (weight: about 60 kg) suffering fromdiabetes (type II diabetes mellitus etc.) ranges usually from about 1 mgto 1 g per day using, as an active ingredient, a compound or apharmaceutically acceptable salt thereof in the present invention. Suchquantity can be administrated to the patient once or in several times aday.

The pharmaceutical composition comprising a compound or apharmaceutically acceptable salt thereof in the present invention as anactive ingredient or an activator, and the kits (administration,treatment and/or prevention kit), packages (packaging goods etc.), andmedicine set (and/or, container) containing the package insert about thepharmaceutical composition which indicate that the pharmaceuticalcomposition can be used or should be used for treatment and/orprevention are also useful. Such kit, the package, and the medicine setmay be provided with one or more containers filled with one or moreactive ingredients and other medicines, or the medicine (or thecomponent) for the above-mentioned pharmaceutical compositions. Asexamples of such a kit, a package, and a medicine set, the kit forcommerce appropriately directed to the treatment and/or prevention of anobject disease and the package for commerce are included. As a packageinsert comprised in such a kit, a package, and a medicine set, notes bythe government organization which regulates manufacture, use or sale ofa pharmaceutical or biological products, and notes which show theapproval of the government organization about manufacture, use or saleof the product relevant to medication to a human are included. In theabove-mentioned kit, package and medicine set, the packed product mayalso be included, and the structure constituted by adopting a suitablemedication step (step) may be included, and the structure constituted ascould attain the treatment and/or prevention on more preferable medicineincluding treatment, prevention of an object disease may be included.

A compound or a pharmaceutically acceptable salt thereof in the presentinvention may be used by the general method currently performed in themedicinal field in combination (henceforth “combination therapy”) withone or multiple other drugs (henceforth, a “concomitant drug”).

A timing for administration of a compound or a pharmaceuticallyacceptable salt thereof in the present invention and a concomitant drugis not limited. They may be administrated to the patient as acombination drug, or they may be administrated to the patientsimultaneously or in a constant interval. A pharmaceutical kit which ischaracterized in consisting of a pharmaceutical composition of thepresent invention and a concomitant drug can be used. The dose of aconcomitant drug should comply with the dose in clinical use, and it canbe selected suitably depending on patients, disease, symptoms, dosageforms, routes of administration, administration time, combination. Theadministration method of a concomitant drug is not limited inparticular, and a compound or a salt thereof in the present inventionand a concomitant drug should just be put together.

The concomitant drug includes, for example,

(1) a therapeutic agent and/or prophylactic of dyslipidemia,(2) a therapeutic agent and/or prophylactic of obesity,(3) a therapeutic agent and/or prophylactic of diabetes,(4) a therapeutic agent and/or prophylactic of diabetic complication,and(5) a therapeutic agent and/or prophylactic of hypertension,and any one or multiple of these agents and a compound or apharmaceutically acceptable salt thereof in the present invention may beused in combination.

As an example, a method for preparing compounds for working the presentinvention is explained as follows, and the method for preparing acompound or a pharmaceutically acceptable salt thereof in the presentinvention is not intended to be limited thereto.

Unless otherwise specified, effective preparation methods may be carriedout by devising such as: introducing any protecting groups into anyfunctional groups, if needed, and then deprotecting at a later step; ineach step, treating any functional groups in the forms of theirprecursor, and converting the same into the corresponding desirablefunctional groups at an appropriate step; interchanging the order ofeach preparation method and step; optionally using reagents other thanthose illustrated below in order to accelerate the progress of reaction,etc.

In each step, aftertreatment of reaction may be performed in aconventional manner, and isolation and purification may be optionallyperformed by selection from or combination of the conventionalprocedures, such as crystallization, re-crystallization, distillation,liquid separation, silica gel column chromatography and preparativeHPLC, if needed. A reaction may be proceeded to the sequential stepwithout isolation and purification depending on the situation.

[Preparation Method 1]

A method for preparing a compound of the general formula [I] isillustrated as “Preparation Method 1-1” and “Preparation Method 1-2”below. Preparation Method 1-1

wherein each symbol has the same meaning as defined above.

(Step 1)

Compound [I] may be obtained by reacting Compound [1] or a salt thereofwith Compound [2] in a solvent in the presence of a condensing agent andan additive.

A preferable condensing agent is dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl),diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP), diphenylphosphoryl azide, etc.

A preferable additive is 1-hydroxybenzotriazole (HOBt),1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu).Optionally, 4-dimethylaminopyridine, etc. may be added as an additive,etc.

A preferable solvent is a halogenated hydrocarbon solvent such aschloroform; an ether solvent such as tetrahydrofuran; a polar solventsuch as pyridine, acetonitrile and N,N-dimethylformamide; or a mixedsolvent thereof.

The reaction temperature is usually about 0° C. to 100° C., preferablyabout 0° C. to 40° C.

When a salt of Compound [1] is used, the reaction may be done in thepresence of a base such as an organic base such as triethylamine; or analkali metal salt such as sodium carbonate.

Alternatively, Compound [I] may be obtained by preliminarily convertingCompound [2] into an acid chloride thereof, etc., and then reacting theresulting compound with Compound [1] in the presence of a base.

Compound [2] may be commercially available, or may be obtained by usingPreparation Method 3 below or a conventional method.

Preparation Method 1-2

wherein, P^(N1) is a protecting group of an amino group; a preferableP^(N1) is tert-butoxycarbonyl group;and each of other symbols has the same meaning as defined above.

(Step 1)

Compound [4] may be obtained by reacting Compound [1] or a salt thereofwith Compound [3] in a solvent in the presence of a condensing agent andan additive.

A preferable condensing agent is dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl),diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP), diphenylphosphoryl azide, etc.

A preferable additive is 1-hydroxybenzotriazole (HOBt),1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), etc.Optionally, 4-dimethylaminopyridine, etc. may be added as an additive,etc.

A preferable solvent is a halogenated hydrocarbon solvent such aschloroform; an ether solvent such as tetrahydrofuran; a polar solventsuch as pyridine, acetonitrile and N,N-dimethylformamide; or a mixedsolvent thereof.

The reaction temperature is usually about 0° C. to 100° C., preferablyabout 0° C. to 40° C.

When a salt of Compound [1] is used, the reaction may be done in thepresence of a base such as an organic base such as triethylamine; or analkali metal salt such as sodium carbonate.

Alternatively, Compound [4] may be obtained by preliminarily convertingCompound [3] into an acid chloride thereof, etc., and then reacting theresulting compound with Compound [1] in the presence of a base.

Compound [3] may be commercially available, or may be obtained by aconventional method.

(Step 2)

Compound [5] or a salt thereof may be obtained by removing P^(N1) fromCompound [4] in a conventional deprotection reaction. The deprotectionreaction may be done by using suitable conditions for each of kinds ofP^(N1). For example, when P^(N1) is tert-butoxycarbonyl group, Compound[5] or a salt thereof may be obtained by treating Compound [4] in asolvent under an acidic condition at room temperature. Compound [5] maybe isolated as a salt, or as a free form after neutralization.

A preferable solvent is, for example, an alcoholic solvent such asethanol; an ether solvent such as 1,4-dioxane; an ester solvent such asethyl acetate; a halogenated hydrocarbon solvent such as chloroform; ora mixed solvent thereof.

A preferable acid used in the reaction is hydrochloric acid ortrifluoroacetic acid.

(Step 3)

Compound [Ia] may be obtained by transforming diamino group of Compound[5] or a salt thereof into urea group.

The reagents used in the reaction include, for example, diethylcarbonate, diethyl pyrocarbonate, 1,1′-carbonyldiimidazole (CDI),chloroformate, etc., preferably 1,1′-carbonyldiimidazole (CDI).

A preferable solvent is a halogenated hydrocarbon solvent such aschloroform; an ether solvent such as tetrahydrofuran; a hydrocarbonsolvent such as toluene; a polar solvent such as pyridine, acetonitrileand N,N-dimethylformamide; or a mixed solvent thereof.

The reaction temperature is usually about 0° C. to 100° C., preferablyabout 0° C. to 40° C.

When a salt of Compound [5] is used, the reaction may be done in thepresence of a base such as an organic base such as triethylamine; or analkali metal salt such as sodium carbonate.

When Compound [I] or Compound [Ia] has an enantiomer or a geometricisomer thereof, the reaction may be done by using a commerciallyavailable optically active compound or a single diastereomer compound orsuch a compound obtained by a conventional method. Alternatively, theoptically active compound or the single diastereomer of Compound [I] orCompound [Ia] may be obtained by separating and purifying appropriatelyduring the preparation process. The compound which undergoes separationand purification includes Compound [I] or Compound [Ia], etc. A methodfor separation and purification includes, for example, columnchromatography or preparative HPLC.

A method for preparing the compound represented by the general Formula[Ib] is illustrated in the following Preparation Method 1-3.

Preparation Method 1-3

wherein, each symbol has the same meaning as defined above.

(Step 1)

Similarly to Preparation Method 1-1 Step 1, Compound [Ib] or a saltthereof may be obtained.

Compound [2d] or a salt thereof may be commercially available, or it canbe obtained by the following Preparation Method 3 or a conventionalmethod.

When Compound [Ib] has an enantiomer or a geometric isomer thereof, thereaction may be done by using a commercially available optically activecompound or a single diastereomer compound or such a compound obtainedby a conventional method. Alternatively, the optically active compoundor single diastereomer of Compound [Ib] may be obtained by separatingand purifying during the preparation process. The compound whichundergoes separation and purification includes Compound [Ib], etc. Amethod for separation and purification includes, for example, columnchromatography, preparative HPLC.

[Preparation Method 2]

A method for preparing Compound [1] is illustrated as Preparation Method2-1 to 2-3″ below.

Preparation Method 2-1

wherein, each symbol has the same meaning as defined above.

(Step 1)

Compound [9] may be obtained by subjecting Compound [8] to Wittigreaction or Horner-Wadsworth-Emmons reaction in a solvent in thepresence of a base.

A preferable reagent used in the Wittig Reaction is(cyanomethyl)triphenylphosphonium chloride, and a preferable reagentused in the Horner-Wadsworth-Emmons reaction is diethylcyanomethylphosphonate.

The base includes, for example, an organic base such as triethylamine;or an alkali metal base such as sodium hydride, potassium tert-butoxide,sodium carbonate and lithium hexamethyldisilazide (LiHMDS), preferablypotassium tert-butoxide.

A preferable solvent is, for example, an ether solvent such astetrahydrofuran; a hydrocarbon solvent such as toluene; a polar solventsuch as N,N-dimethylformamide; or a mixed solvent thereof.

The reaction temperature is usually about −78° C. to 100° C., preferablyabout 0° C. to 40° C.

Compound [8] may be commercially available, or obtained by aconventional method.

(Step 2)

Compound [11] or a salt thereof may be obtained by reacting Compound [9]with Compound [10] or a salt thereof in a solvent in the presence of abase.

The base used in the reaction includes, for example, an organic basesuch as triethylamine; and an alkali metal base such as sodium hydride,sodium ethoxide, potassium tert-butoxide, sodium carbonate or lithiumhexamethyldisilazide (LiHMDS), preferably sodium ethoxide.

A preferable solvent is an alcoholic solvent such as ethanol; an ethersolvent such as tetrahydrofuran; a hydrocarbon solvent such as toluene;a polar solvent such as N,N-dimethylformamide; or a mixed solventthereof.

The reaction temperature is usually about 0° C. to 150° C., preferablyabout 20° C. to 100° C.

Compound [10] or a salt thereof may be commercially available, or may beobtained by a conventional method.

(Step 3)

Compound [1] or a salt thereof may be obtained by reacting Compound [11]or a salt thereof with an oxidizing agent in a solvent.

A preferable oxidizing agent is 2,3-dichloro-5,6-dicyano-p-benzoquinone(DDQ), p-chloranil, Oxone (Registered Trademark), manganese dioxide,activated carbon, oxygen gas, etc.

A preferable solvent is, for example, an ether solvent such as dioxane;a polar solvent such as N,N-dimethylformamide; a hydrocarbon solventsuch as toluene; a halogenated hydrocarbon solvent such as chloroform;or a mixed solvent thereof.

The reaction temperature is usually about 0° C. to 150° C., preferablyabout 20° C. to 150° C.

Preparation Method 2-2

wherein, P^(N2) is hydrogen atom or a protecting group of amino group;preferably, two P^(N2)s are combined together with the nitrogen atom towhich they are attached to form 2,5-dimethylpyrrole; L¹ is a leavinggroup, preferably bromine atom or iodine atom; each of the other symbolshas the same meaning as defined above.

(Step 1)

Compound [13] or a salt thereof may be obtained by the same procedure asStep 3 of Preparation Method 2-1.

Compound [12] or a salt thereof may be commercially available, or may beobtained by a conventional method.

(Step 2)

Compound [14] may be obtained by introducing P^(N2) into amino group ofCompound [13] or a salt thereof by a conventional protection reaction.The protection reaction may be done by using suitable conditions foreach of kinds of P^(N2). For example, when two P^(N2)s together with thenitrogen atom to which they are attached to form 2,5-dimethylpyrrole,Compound [14] may be obtained by reacting with 2,5-hexanedione in asolvent under an acidic condition.

The acid used in the reaction includes, for example, conc. hydrochloricacid, conc. sulfuric acid, amidosulfuric acid, p-toluenesulfonic acid oracetic acid, preferably acetic acid.

A preferable solvent is, for example, an alcoholic solvent such asethanol; an ether solvent such as tetrahydrofuran; a hydrocarbon solventsuch as toluene; a polar solvent such as N,N-dimethylformamide; ahalogenated hydrocarbon solvent such as dichloroethane; or a mixedsolvent thereof. Alternatively, an organic acid such as acetic acid maybe used as the solvent.

The reaction temperature is usually about 0° C. to 150° C., preferablyabout 20° C. to 120° C.

(Step 3)

Compound [15] may be obtained by introducing L¹ into Compound [14] in asolvent in the presence of a base. For example, when L¹ is iodine atom,Compound [15] may be obtained by iodination in a solvent in the presenceof a base.

The base used in the reaction includes, for example, n-butyllithium,lithium hexamethyldisilazide, or lithium tetramethylpiperidide,preferably n-butyllithium.

The iodination agent includes, for example, iodine, iodine monochloride,N-iodosuccinimide or 1-chloro-2-iodoethane, preferably iodine.

A preferable solvent is, for example, an ether solvent such astetrahydrofuran; a hydrocarbon solvent such as toluene; or a mixedsolvent thereof.

The reaction temperature is usually about −100° C. to 40° C., preferablyabout −78° C. to 20° C.

(Step 4)

Compound [16] or a salt thereof may be obtained by removing P^(N2) ofCompound [15] by a conventional deprotection reaction. The deprotectionreaction may be done by using suitable conditions for each of kinds ofP^(N2). For example, when two P^(N2)s are together with the nitrogenatom to which they are attached to form 2,5-dimethylpyrrole, Compound[16] or a salt thereof may be obtained by treating Compound [15] in asolvent in the presence of hydroxylamine. Compound [16] may be isolatedas a salt, or as a free form after neutralization.

A preferable solvent is an alcoholic solvent such as ethanol; water; ora mixed solvent thereof.

The reaction temperature is usually about 40° C. to 150° C., preferablyabout 80° C. to 130° C.

(Step 5)

Compound [1] or a salt thereof may be obtained by treating Compound [16]or a salt thereof and Compound [17] in Suzuki coupling reaction. Forexample, Compound [1] or a salt thereof may be obtained by reactingCompound [16] or a salt thereof with Compound [17] in a solvent underheating in the presence of a base and a palladium catalyst.

The palladium catalyst used in the reaction includes, for example,tetrakis(triphenylphosphine)palladium or(bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloridecomplex.

The base used in the reaction includes potassium phosphate, sodiumcarbonate, sodium hydrogen carbonate, potassium carbonate andtriethylamine, etc.

A preferable solvent is an ether solvent such as 1,4-dioxane,tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; an alcoholicsolvent such as methanol, ethanol, 1-propanol and 2-propanol; ahydrocarbon solvent such as toluene, n-hexane and xylene; a polarsolvent such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile;or a mixed solvent thereof with water.

Compound [17] may be commercially available, or obtained by aconventional method. Alternatively, the reactions in this step may bedone by using boronic acid ester.

By using Compound [12a] and Compound [17a] respectively in place ofCompound [12] and Compound [17], Compound [1a] may be obtained similarlyto the Preparation Method 2-2.

wherein, Compound [17a] is boronic acid ester, and each symbol has thesame meaning as defined above.

Compound [12a] or a salt thereof may be commercially available, or maybe obtained by a conventional method.

Compound [17a] may be commercially available, or may be obtained by aconventional method. The reactions in this step may be carried out byusing boronic acid.

A reagent used for obtaining Compound [17a] includes the followingreagents.

For example, when the ring Cy is C₆₋₁₀ aryl group substituted by aleaving group (preferably chlorine atom, bromine atom, iodine atom,p-toluenesulfonyloxy group, methanesulfonyloxy group ortrifluoromethanesulfonyloxy group) in addition to R^(1a), palladiumcatalysts such as palladium acetate, palladium chloride, andtris(dibenzylideneacetone)dipalladium; organic phosphorous compoundssuch as triphenylphosphine, tricyclohexylphosphine,1,1′-bis(diphenylphosphino)ferrocene,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl; boron compoundssuch as bis(pinacolate)diboron; bases such as potassium acetate, sodiumcarbonate, and potassium carbonate, are included.

For example, when the ring Cy is C₆₋₁₀ aryl group which does not haveany substituent other than R^(1a), iridium reagents such asdi-t-methoxobis(1,5-cyclo)(octadiene)diiridium; bipyridine compoundssuch as 4,4′-di-tert-butyl-2,2′-bipyridine and4,4′-dimethoxy-2,2′-bipyridine; boron compounds such asbis(pinacolate)diboron are included.

Preparation Method 2-3

wherein P^(N2) is hydrogen atom or a protecting group of amino group,preferably, two P^(N2)s combine together with the nitrogen atom to whichthey are attached to form 2,5-dimethylpyrrole; L¹ is a leaving group,preferably bromine atom or iodine atom; L² is a leaving group,preferably chlorine atom, bromine atom, iodine atom, dihydroxyborylgroup, p-toluenesulfonyloxy group or methanesulfonyloxy group; each ofthe other symbols has the same meaning as defined above.

(Step 1)

Compound [19] may be obtained by the same procedure as Step 2 ofPreparation Method 2-2.

(Step 2)

Compound [14] may be obtained by reacting Compound [19] with Compound[20] in a solvent.

For example, when R² is C₁₋₈ alkyl group or C₃₋₈ cycloalkyl group and L²is chlorine atom, bromine atom, iodine atom, p-toluenesulfonyloxy groupor methanesulfonyloxy group, Compound [14] may be obtained by reactingCompound [19] with Compound [20] in a solvent in the presence of a base.

The base used in the reaction includes, for example, potassiumhydroxide, potassium carbonate, sodium ethoxide, potassiumtert-butoxide, sodium hydride, preferably sodium hydride.

A preferable solvent is, for example, an ether solvent such astetrahydrofuran; a polar solvent such as N,N-dimethylformamide; analcoholic solvent such as ethanol; or a mixed solvent thereof.

The reaction temperature is usually about 0° C. to 100° C., preferablyabout 0° C. to 80° C.

For example, when R² is C₆₋₁₀ aryl group and L² is bromine atom oriodine atom, Compound [14] may be obtained by reacting Compound [19]with Compound [20] in a solvent in the presence of a metal reagent, aligand and a base.

The metal reagent used in the reaction includes, for example, copper (I)iodide, copper (I) oxide, cobalt (II) chloride, manganese (II) chlorideor iron (III) chloride, preferably copper (I) oxide.

The ligand used in the reaction includes, for example, salicylaldoxime,trans-1,2-cyclohexanediamine, 8-quinolinol, 1,10-phenanthroline,L-proline, and preferably 8-quinolinol.

The base used in the reaction includes, for example, potassiumhydroxide, tripotassium phosphate, potassium carbonate, cesium carbonateor sodium tert-butoxide, preferably cesium carbonate.

A preferable solvent is, for example, a hydrocarbon solvent such astoluene and xylene; a polar solvent such as acetonitrile andN,N-dimethylformamide; or a mixed solvent thereof.

The reaction temperature is usually about 20° C. to 150° C., preferablyabout 80° C. to 130° C.

For example, when R² is C₆₋₁₀ aryl group and L² is dihydroxyboryl group,Compound [14] may be obtained by reacting Compound [19] with Compound[20] in a solvent in the presence of a copper reagent and a base in airat room temperature.

A preferable copper reagent used in the reaction is copper (II) acetateand copper (I) oxide.

A preferable base used in the reaction is an organic base such aspyridine and triethylamine.

A preferable solvent is, for example, an alcoholic solvent such asmethanol and ethanol; a halogenated hydrocarbon solvent such asdichloromethane and chloroform; or a mixed solvent thereof.

Compound [20] may be commercially available, or may be obtained by aconventional method.

(Step 3)

Compound [15] may be obtained by the same procedure as Step 3 ofPreparation Method 2-2.

(Step 4)

Compound [16] or a salt thereof may be obtained by the same procedure asStep 4 of Preparation Method 2-2.

(Step 5)

Compound [1] or a salt thereof may be obtained by the same procedure asStep 5 of Preparation Method 2-2.

By using Compound [20a] and Compound [17a] respectively in place ofCompound [20] and Compound [17], Compound [1a] may be obtained similarlyto the Preparation Method 2-3.

wherein, each symbol has the same meaning as defined above.

Compound [20a] or a salt thereof may be commercially available, or itmay be obtained by a conventional method.

The reaction in this step may be carried out using boronic acid in placeof Compound [17a].

[Preparation Method 3]

A method for preparing Compound [2] is illustrated as PreparationMethods 3-1 to 3-3 below.

Preparation Method 3-1

wherein, P^(C1) is a protecting group of carboxy group, preferablymethyl group, ethyl group, tert-butyl group or benzyl group; P^(N3) is aprotecting group of amino group, preferably 2,4-dimethoxybenzyl group;carbon atoms with * may be optionally substituted by R³ within thechemically acceptable range; each of the other symbols has the samemeaning as defined above.

(Step 1)

Compound [23] may be obtained by reacting Compound [21] with Compound[22] in a solvent.

A preferable solvent is, for example, a hydrocarbon solvent such astoluene; an alcoholic solvent such as methanol and ethanol; or a mixedsolvent thereof.

The reaction temperature is usually about 20° C. to 150° C., preferablyabout 80° C. to 130° C.

Compound [21] may be commercially available, or may be obtained byAuxiliary Step 1 below or a conventional method. Compound [22] may becommercially available, or obtained by a conventional method.

Auxiliary Step 1

wherein, P^(C1) is a protecting group of carboxy group, preferablymethyl group, ethyl group, tert-butyl group or benzyl group; m1 is 0, 1,2 or 3; L³ is a leaving group, preferably, bromine atom; carbon atomswith * may be optionally substituted by R³ within the chemicallyacceptable range; each of the other symbols has the same meaning asdefined above.

(Auxiliary Step 1-1)

Compound [26] may be obtained by introducing L³ into Compound [25]. Forexample, when L³ is bromine atom, Compound [26] may be obtained bybrominating in a solvent in the presence of a radical reactioninitiator.

A preferable radical reaction initiator is azobisisobutyronitrile(AIBN).

A preferable brominating agent is N-bromosuccinimide (NBS).

A preferable solvent is a halogenated hydrocarbon solvent such asdichloromethane and carbon tetrachloride.

The reaction temperature is usually about 20° C. to 130° C., preferablyabout 40° C. to 100° C.

Compound [25] may be commercially available, or may be obtained by aconventional method.

(Auxiliary Step 1-2)

Compound [21a] may be obtained by introducing R³ into Compound [26]. Forexample, Compound [21a] may be obtained by reacting Compound [26] with aGrignard reagent in a solvent in the presence of an additive.

A preferable additive is hexamethylphosphoric triamide (HMPA).

A preferable solvent is, for example, an ether solvent such as diethylether and tetrahydrofuran; a polar solvent such asN,N-dimethylformamide; or a mixed solvent thereof.

The reaction temperature is usually about −78° C. to 40° C., preferablyabout −20° C. to 25° C.

The Grinard reagent may be commercially available, or may be obtained bya conventional method.

(Step 2)

Compound [24] or a salt thereof may be obtained by removing P^(C1) ofCompound [23] by a conventional deprotection reaction. The deprotectionreaction may be done by using suitable conditions for each of kinds ofP^(C1). For example, when P^(C1) is methyl group, Compound [24] or asalt thereof may be obtained by hydrolyzing Compound [23] in a solventin the presence of a base.

The base includes, for example, lithium hydroxide, sodium hydroxide,potassium hydroxide, sodium methoxide, preferably sodium hydroxide.

A preferable solvent is, for example, an alcoholic solvent such asmethanol; an ether solvent such as tetrahydrofuran; water; or a mixedsolvent thereof.

The reaction temperature is usually about 0° C. to 100° C., preferablyabout 0° C. to 40° C.

(Step 3)

Compound [2a] or a salt thereof may be obtained by removing P^(N3) ofCompound [24] or a salt thereof by a conventional deprotection reaction.The deprotection reaction may be done by using suitable conditions foreach of kinds of P^(N3). For example, when P^(N3) is 2,4-dimethoxybenzylgroup, Compound [2a] or a salt thereof may be obtained by treating withan acid in a solvent in the presence of an additive.

The acid includes, for example, methanesulfonic acid, p-toluenesulfonicacid, trifluoroacetic acid, preferably trifluoroacetic acid.

The additive includes, for example, anisole and triethylsilane;preferably anisole.

A preferable solvent is, for example, a halogenated hydrocarbon solventsuch as dichloromethane; a hydrocarbon solvent such as toluene; water;or a mixed solvent thereof. Alternatively, an organic acid such astrifluoroacetic acid may be used as the solvent.

The reaction temperature is usually about 0° C. to 130° C., preferablyabout 25° C. to 80° C.

When Compound [2a] has geometric isomers, a single diastereomer may beobtained by separating and purifying appropriately during thepreparation process. The compound which undergoes separation andpurification includes Compound [23], etc. A method for separation andpurification includes, for example, column chromatography, orpreparative HPLC. Alternatively, separation and purification may be doneafter increasing diastereomer excess ratio of a preferable configurationby subjecting Compound [23] to a basic condition.

Enantiomers resulted from an asymmetric carbon atom in the α-position ofcarboxy group of Compound [2a] may be separated and purified as a singlediastereomer by introducing a chiral auxiliary to give an opticallyactive compound thereof. For example, Compounds [2a_chiral_1] and[2a_chiral_2] may be obtained by using (R)-4-benzyl-2-oxazolidinone asthe chiral auxiliary for Compound [24] or a salt thereof as shown inAuxiliary Step 2 below.

Auxiliary Step 2

wherein, carbon atoms with * may be optionally substituted by R³ withinthe chemically acceptable range; each of the other symbols has the samemeaning as defined above.

(Auxiliary Step 2-1)

Compound [27_chiral_1] and Compound [27_chiral_2] may be obtained byreacting Compound [24] or a salt thereof with(R)-4-benzyl-2-oxazolidinone in a solvent in the presence of acondensing agent and an additive. At this stage, Compound [27_chiral_1]and Compound [27_chiral_2] may be separated and purified by silica gelcolumn chromatography. A preferable condensing agent isdicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl),etc.

A preferable additive is 4-dimethylaminopyridine, etc.

A preferable solvent is a halogenated hydrocarbon solvent such aschloroform, etc.

The reaction temperature is usually about 0° C. to 100° C., preferablyabout 0° C. to 40° C.

Alternatively, Compound [27_chiral_1] and Compound [27_chiral_2] may beobtained by preliminarily converting Compound [24] into an acid chloridethereof, etc., and then reacting the resulting compound with(R)-4-benzyl-2-oxazolidinone in the presence of a base.

(Auxiliary Step 2-2)

Compound [24_chiral_1] or a salt thereof (or Compound [24_chiral_2] or asalt thereof) may be obtained by reacting Compound [27_chiral_1] (orCompound [27_chiral_2]) in a solvent in the presence of a base and anaqueous hydrogen peroxide.

The base used in the reaction includes, for example, sodium hydroxide,lithium hydroxide, preferably lithium hydroxide.

A preferable solvent is, for example, an ether solvent such astetrahydrofuran; water; or a mixed solvent thereof.

The reaction temperature is usually about 0° C. to 50° C., preferablyabout 0° C. to 25° C.

(Auxiliary Step 2-3)

Compound [2a_chiral_1] or a salt thereof (or Compound [2a_chiral_2] or asalt thereof) may be obtained by the same procedure as Step 3 ofPreparation Method 3-1.

Preparation Method 3-2

wherein, carbon atoms with * may be optionally substituted by R³ withinthe chemically acceptable range; each of the other symbols has the samemeaning as defined above.

(Step 1)

Compound [29] or a salt thereof may be obtained by treating Compound[28] or a salt thereof with bromine, followed by a base in a solvent.

The base includes, for example, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate, triethylamine, preferably sodium hydrogencarbonate or sodium carbonate.

A preferable solvent is, for example, a halogenated hydrocarbon solventsuch as dichloromethane, carbon tetrachloride; water.

The reaction temperature is usually about 0° C. to 100° C., preferablyabout 25° C. to 80° C.

Compound [28] or a salt thereof may be commercially available, or may beobtained by a conventional method.

(Step 2)

Compound [2b] or a salt thereof may be obtained by reducting Compound[29] or a salt thereof by a catalytic hydrogenation in a solvent in thepresence of a metal catalyst under hydrogen atmosphere.

The metal catalyst includes, for example, palladium on carbon,alumina-supported rhodium, Raney nickel, Adams' catalyst, preferablypalladium on carbon.

A preferable solvent is, for example, an alcoholic solvent such asmethanol and ethanol; an ether solvent such as tetrahydrofuran; an estersolvent such as ethyl acetate; water, or a mixed solvent thereof.

The reaction temperature is usually about 25° C. to 80° C., preferablyabout 25° C. to 50° C.

Preparation Method 3-3

wherein, P^(N4) is a protecting group of amino group, preferablybenzyloxycarbonyl group; P^(C3) is a protecting group of carboxy group,preferably methyl group, ethyl group, tert-butyl group or benzyl group;R^(4a) is C₁₋₆ alkyl group; L⁴ is a leaving group, preferably halogenatom; carbon atoms with * may be optionally substituted by R³ within thechemically acceptable range; each of the other symbols has the samemeaning as defined above.

(Step 1)

Compound [31] or a salt thereof may be obtained by subjecting Compound[30] or a salt thereof to Hofmann rearrangement reaction in the presenceof a base and bromine, followed by intramolecular cyclization reactionin a solvent.

The base includes, for example, sodium hydroxide, potassium hydroxide,sodium methoxide, preferably sodium hydroxide.

A preferable solvent is, for example, an alcoholic solvent such asmethanol and ethanol; an ether solvent such as 1,4-dioxane; water; or amixed solvent thereof.

The reaction temperature is usually about −78° C. to 100° C., preferablyabout −40° C. to 80° C.

Compound [30] or a salt thereof may be commercially available, or may beobtained by a conventional method.

(Step 2)

Compound [32] may be obtained by introducing P^(C3) into carboxy groupof Compound [31] or a salt thereof by a conventional protectionreaction. The protection reaction may be done by using suitableconditions for each of kinds of P^(C3). For example, P^(C3) istert-butyl group, Compound [32]may be obtained by preliminarilyconverting Compound [31] into an acid chloride thereof in a solvent,etc., and then reacting the resulting compound with tert-butyl alcoholin the presence of a base

The reagent used in the reaction is, for example, thionyl chloride,oxalyl chloride, phosphorous oxychloride, preferably phosphorousoxychloride.

The base includes, for example, an organic amine such as triethylamineand pyridine; an alkali metal carbonate such as sodium carbonate,potassium carbonate and sodium hydrogen carbonate, preferably pyridine.

A preferable solvent is, for example, a hydrocarbon solvent such astoluene; an ether solvent such as tetrahydrofuran; a halogenatedhydrocarbon solvent such as chloroform; or a mixed solvent thereof.

The reaction temperature is usually about 0° C. to 130° C., preferablyabout 25° C. to 80° C.

(Step 3)

Compound [34] may be obtained by rearranging P^(N4) of Compound [32],followed by introducing R^(4a) into the rearranged compound in a solventin the presence of a base.

A preferable base is sodium hydride.

A preferable solvent is, for example, an ether solvent such astetrahydrofuran; a polar solvent such as N,N-dimethylformamide; or amixed solvent thereof.

The reaction temperature is usually about 0° C. to 80° C., preferablyabout 0° C. to 25° C.

Compound [33] may be commercially available, or may be obtained by aconventional method.

(Step 4)

Compound [35] may be obtained by removing P^(N4) from Compound [34] by aconventional deprotection reaction. The deprotection reaction may bedone by using suitable conditions for each of kinds of P^(N4). Forexample, when P^(N4) is benzyloxycarbonyl group, Compound [35] may beobtained by reducting Compound [34] by a catalytic hydrogenation in asolvent in the presence of a palladium catalyst under hydrogenatmosphere.

The palladium catalyst includes, for example, palladium on carbon,palladium (II) hydroxide, preferably palladium on carbon.

A preferable solvent is, for example, an alcoholic solvent such asmethanol; an ether solvent such as tetrahydrofuran; an ester solventsuch as ethyl acetate; or a mixed solvent thereof.

The reaction temperature is usually about 25° C. to 80° C., preferablyabout 25° C. to 50° C.

(Step 5)

Compound [2c] or a salt thereof may be obtained by removing P^(C3) fromCompound [35] by a conventional deprotection reaction. The deprotectionreaction may be done by using suitable conditions for each of kinds ofP^(C3). For example, when P^(C3) is tert-butyl group, Compound [2c] maybe obtained by treating Compound [35] in a solvent under an acidiccondition.

The acid includes, for example, hydrochloric acid, sulfuric acid,trifluoroacetic acid, preferably trifluoroacetic acid.

A preferable solvent is, for example, an ether solvent such as1,4-dioxane; a halogenated hydrocarbon solvent such as chloroform; anester solvent such as ethyl acetate; an alcoholic solvent such asmethanol; water; or a mixed solvent thereof.

The reaction temperature is usually about 0° C. to 80° C., preferablyabout 0° C. to 40° C.

When Compound [2c] has an enantiomer thereof, the reaction may be doneby using a commercially available optically active compound or using aproduct obtained therefrom by a conventional method.

Preparation Method 3-4

wherein, carbon atoms indicated by * in the Formula may be optionallysubstituted by R^(3a) within the chemically acceptable range, each ofthe other symbols has the same meaning as defined above.

(Step 1)

Compound [37] or a salt thereof may be obtained by the same procedure asStep 1 of Preparation Method 3-3.

Compound [36] or a salt thereof may be commercially available, or may beobtained by a conventional method.

(Step 2)

Compound [2d] or a salt thereof may be obtained by the same procedure asStep 4 of Preparation Method 3-3.

When Compound [2d] has an enantiomer thereof, the reaction may becarried out by using a commercially available optically active compoundor using a product obtained therefrom by a conventional method.

Preparation Method 3-5

wherein, P^(N5) is a protecting group of amino group, preferablybenzyloxycarbonyl group; carbon atoms indicated by * may be optionallysubstituted by R^(3a) within the chemically acceptable range; each ofthe other symbols has the same meaning as defined above.

(Step 1)

Compound [2e] or a salt thereof may be obtained by reacting Compound[38] or a salt thereof in the presence of a base in a solvent.

The base includes, for example, sodium hydroxide, potassium hydroxide,sodium methoxide, preferably sodium hydroxide.

A preferable solvent is, for example, an alcoholic solvent such asmethanol and ethanol; an ether solvent such as 1,4-dioxane; water; or amixed solvent thereof.

The reaction temperature is usually about 0 to 100° C., preferably about25 to 50° C.

Compound [38] or a salt thereof may be commercially available, or may beobtained by a conventional method.

When Compound [2e] has an enantiomer thereof, the reaction may becarried out using a commercially available optically active compound orusing a product obtained therefrom by a conventional method.

Preparation Method 3-6

wherein, P^(C4) is a protecting group of carboxy group, preferablymethyl group, ethyl group, tert-butyl group, or benzyl group; carbonatoms indicated by * may be optionally substituted by R^(3a) within thechemically acceptable range; each of the other symbols has the samemeaning as defined above.

(Step 1)

Compound [40] may be obtained by subjecting Compound [39] or a saltthereof to Curtius rearrangement reaction, followed by an intramolecularcyclization reaction in a solvent.

The reagent used for the reaction includes, for example,diphenylphosphoryl azide.

A preferable solvent is, for example, a hydrocarbon solvent such astoluene; an alcoholic solvent such as ethanol and tert-butanol; an ethersolvent such as 1,4-dioxane; or a mixed solvent thereof.

The reaction temperature is usually about 40 to 140° C., preferablyabout 80 to 120° C.

Compound [39] or a salt thereof may be commercially available, or may beobtained by a conventional method.

(Step 2)

Compound [2e] or a salt thereof may be obtained by removing P^(C4) ofCompound [40] by a conventional deprotection reaction. The deprotectionreaction may be carried out using suitable conditions for each of kindsof P^(C4), for example, when P^(C4) is benzyl group, Compound [2e] or asalt thereof may be obtained by reducting Compound [40] by a catalytichydrogenation in the presence of a palladium catalyst in a solvent underhydrogen atmosphere.

The palladium catalyst includes, for example, palladium on carbon,palladium (II) hydroxide, preferably palladium on carbon.

A preferable solvent is an alcoholic solvent such as methanol; an ethersolvent such as tetrahydrofuran; an ester solvent such as ethyl acetate;or a mixed solvent thereof.

The reaction temperature is usually about 25 to 80° C., preferably about25 to 50° C.

When Compound [2e] has an enantiomer thereof, the reaction may becarried out using a commercially available optically active compound orusing a product obtained therefrom by a conventional method.

Preparation Method 3-7

wherein, P^(C5) is a protecting group of carboxy group, preferablymethyl group, ethyl group, tert-butyl group or benzyl group; carbonatoms indicated by * may be optionally substituted by R^(3a) within thechemically acceptable range; each of the other symbols has the samemeaning as defined above.

(Step 1)

Compound [42] may be obtained by reacting Compound [41] with Compound[22] in a solvent. Compound [22] itself may be used as a solvent.

A preferable solvent is, for example, a hydrocarbon solvent such astoluene; an alcoholic solvent such as methanol and ethanol; or a mixedsolvent thereof.

The reaction temperature is usually about 20 to 150° C., preferablyabout 80 to 130° C.

Compound [41] may be commercially available, or may be obtained by aconventional method.

Compound [22] may be commercially available, or may be obtained by aconventional method.

(Step 2)

Compound [43] may be obtained by converting amino group and hydroxygroup of Compound [42] into carbamate group in a solvent.

The reagent used for the reaction includes, for example,diethylcarbonate, diethylpyrocarbonate, 1,1′-carbonyldiimidazole (CDI),chloroformate, preferably 1,1′-carbonyldiimidazole (CDI).

A preferable solvent is, for example, a halogenated hydrocarbon solventsuch as chloroform; an ether solvent such as tetrahydrofuran; ahydrocarbon solvent such as toluene; a polar solvent such as pyridine,acetonitrile and N,N-dimethylformamide; or a mixed solvent thereof.

The reaction temperature is usually about 0 to 100° C., preferably about0 to 40° C.

(Step 3).

Compound [2f] or a salt thereof may be obtained by removing P^(N3) andP^(C5) of Compound [43] by a conventional deprotection reaction. Thedeprotection reaction may be carried out using suitable conditions foreach of kinds of P^(N3) and P^(C5), and for example, when P^(N3) is2,4-dimethoxybenzyl group and P^(C5) is tert-butyl group, Compound [2f]or a salt thereof may be obtained by treating with an acid in thepresence of an additive in a solvent.

The acid includes, for example, methanesulfonic acid, p-toluenesulfonicacid, trifluoroacetic acid, preferably trifluoroacetic acid.

The additive includes, for example, anisole, triethylsilane, preferablyanisole.

A preferable solvent is, for example, a halogenated hydrocarbon solventsuch as dichloromethane; a hydrocarbon solvent such as toluene; water;or a mixed solvent thereof. The organic acid itself such astrifluoroacetic acid may be used as a solvent.

The reaction temperature is usually about 0 to 130° C., preferably about25 to 80° C.

Preparation Method 3-8

wherein, P^(C6) is a protecting group of carboxy group, preferablymethyl group, ethyl group, tert-butyl group or benzyl group; L⁶ is aleaving group, preferably chlorine atom or bromine atom; carbon atomsindicated by * may be optionally substituted by R^(3a) within thechemically acceptable range; each of the other symbols has the samemeaning as defined above.

(Step 1)

Compound [45] may be obtained by reacting Compound [44] with Compound[22] in a solvent. Compound [22] itself may be used as a solvent.

A preferable solvent is, for example, a hydrocarbon solvent such astoluene; an alcoholic solvent such as ethanol and tert-butanol; a polarsolvent such as acetonitrile and N,N-dimethylformamide; or a mixedsolvent thereof.

The reaction temperature is usually about 20 to 150° C., preferablyabout 80 to 130° C.

Compound [44] may be commercially available, or may be obtained by aconventional method.

(Step 2)

Compound [47] may be obtained by reacting Compound [45] with Compound[46] in the presence of a base in a solvent.

The base includes, for example, an organic amine such as triethylamineand pyridine; an alkali metal carbonate such as sodium carbonate,potassium carbonate and sodium hydrogen carbonate, preferablytriethylamine.

A preferable solvent is, for example, a hydrocarbon solvent such astoluene; an ether solvent such as tetrahydrofuran; a halogenatedhydrocarbon solvent such as chloroform; a polar solvent such asacetonitrile; or a mixed solvent thereof.

The reaction temperature is usually about −20 to 130° C., preferablyabout 0 to 80° C.

Compound [48] may be commercially available, or may be obtained by aconventional method.

(Step 3)

Compound [48] may be obtained by reacting Compound [47] in the presenceof a base in a solvent.

The base includes, for example, an alkali metal carbonate such as sodiumcarbonate, potassium carbonate and cesium carbonate; potassiumtert-butoxide, sodium hydride, preferably potassium tert-butoxide.

The solvent includes, for example, a hydrocarbon solvent such astoluene; an ether solvent such as tetrahydrofuran; an alcoholic solventsuch as tert-butanol; a polar solvent such as N,N-dimethylformamide; ora mixed solvent thereof.

The reaction temperature is usually about 0 to 130° C., preferably about25 to 80° C.

(Step 4)

Compound [59] or a salt thereof may be obtained by the same procedure asStep 2 of Preparation Method 3-1.

(Step 5)

Compound [2g] or a salt thereof may be obtained by the same procedure asStep 3 of Preparation Method 3-1.

An enantiomer derived from an asymmetric carbon atom of the alphaposition of carboxy group of Compound [2g] may be obtained by the sameprocedure as Auxiliary step 2 of Preparation Method 3-1.

Preparation Method 3-9

wherein, P^(C7) is a protecting group of carboxy group, preferablymethyl group, ethyl group, tert-butyl group or benzyl group; P^(C8) is aprotecting group of carboxy group, preferably methyl group, ethyl group,tert-butyl group or benzyl group; P^(C9) is a protecting group ofcarboxy group, preferably methyl group, ethyl group, tert-butyl group orbenzyl group; P^(N6) is a protecting group of amino group, preferablytert-butoxycarbonyl group; P^(N7) is a protecting group of amino group,preferably benzyloxycarbonyl group: L⁷ is a leaving group, preferablychlorine atom or bromine atom: carbon atoms indicated by * may beoptionally substituted by R^(3a) within the chemically acceptable range;each of the other symbols has the same meaning as defined above.

(Step 1)

Compound [52] or a salt thereof may be obtained by reacting Compound[50] or a salt thereof with Compound [51] in the presence of a base in asolvent.

The base includes, for example, an organic amine such as triethylamineand pyridine; an alkali metal carbonate such as sodium carbonate,potassium carbonate and sodium hydrogen carbonate, preferably potassiumcarbonate.

A preferable solvent is, for example, a hydrocarbon solvent such astoluene; an ether solvent such as tetrahydrofuran; a halogenatedhydrocarbon solvent such as chloroform; a polar solvent such asacetonitrile; or a mixed solvent thereof.

The reaction temperature is usually about 0 to 130° C., preferably about25 to 80° C.

Compound [50] or a salt thereof may be commercially available, or may beobtained by a conventional method. Compound [51] may be commerciallyavailable, or may be obtained by a conventional method.

(Step 2)

Compound [53] or a salt thereof may be obtained by removing P^(C8) ofCompound [52] or a salt thereof by a conventional deprotection reaction.The deprotection reaction may be carried out using suitable conditionsfor each of kinds of P^(C8), for example, when P^(C3) is tert-butylgroup, Compound [53] or a salt thereof may be obtained by the sameprocedure as Step 5 of Preparation Method 3-3.

(Step 3)

Compound [54] or a salt thereof may be obtained by introducing P^(N6)into amino group of Compound [53] or a salt thereof by a conventionalprotection reaction. The protection reaction may be carried out usingsuitable conditions for each of kinds of P^(N6), for example, whenP^(N6) is tert-butoxycarbonyl group, Compound [54] or a salt thereof maybe obtained by reacting with di-tert-butyl dicarbonate in the presenceof a base in a solvent.

The base includes, for example, an organic amine such as triethylamineand pyridine; an alkali metal carbonate such as sodium carbonate,potassium carbonate and sodium hydrogen carbonate, preferablytriethylamine.

A preferable solvent is, for example, a hydrocarbon solvent such astoluene; an ether solvent such as tetrahydrofuran; a halogenatedhydrocarbon solvent such as chloroform; a polar solvent such asacetonitrile; water; or a mixed solvent thereof.

The reaction temperature is usually about 0 to 130° C., preferably about25 to 50° C.

(Step 4)

Compound [55] may be obtained by subjecting Compound [54] or a saltthereof to Curtius rearrangement reaction in the presence of an alcoholin a solvent.

The reagent used for the reaction includes, for example,diphenylphosphoryl azide.

The alcohol used for the reaction includes, for example, benzyl alcohol,tert-butanol, preferably benzyl alcohol.

A preferable solvent is, for example, a hydrocarbon solvent such astoluene; an ether solvent such as 1,4-dioxane; or a mixed solventthereof.

The reaction temperature is usually about 25 to 140° C., preferablyabout 80 to 120° C.

(Step 5)

Compound [56] or a salt thereof may be obtained by removing P^(N7) andP^(C9) of Compound [55] by a conventional deprotection reaction. Thedeprotection reaction may be carried out using suitable conditions foreach of kinds of P^(N7) and P^(C9), for example, when P^(N7) isbenzyloxycarbonyl group and P^(C9) is benzyl group, Compound [58] or asalt thereof may be obtained by reducting Compound [57] by a catalytichydrogenations in the presence of a metal catalyst in a solvent underhydrogen atmosphere.

The metal catalyst includes, for example, palladium on carbon, palladiumblack, palladium (II) hydroxide, preferably palladium on carbon.

A preferable solvent is, for example, an alcoholic solvent such asmethanol and ethanol; an ether solvent such as tetrahydrofuran an estersolvent such as ethyl acetate water or a mixed solvent thereof.

The reaction temperature is usually about 25 to 80° C., preferably about25 to 50° C.

(Step 6)

Compound [57] may be obtained by reacting Compound [56] or a saltthereof in the presence of a condensing agent and an additive in asolvent.

A preferable condensing agent is dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl),diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hcxafluorophosphate(PyBOP) or diphenylphosphoryl azide, etc.

A preferable additive is 1-hydroxybenzotriazol (HOBt),1-hydroxy-7-azabenzotriazol (HOAt), N-hydroxysuccinimide (HOSu), etc.4-Dimethylaminopyridine etc. may be optionally added as an additive.

A preferable solvent is a halogenated hydrocarbon solvent such aschloroform; an ether solvent such as tetrahydrofuran; a polar solventsuch as pyridine, acetonitrile and N,N-dimethylformamide; or a mixedsolvent thereof.

The reaction temperature is usually about 0 to 100° C., and preferablyis about 0 to 40° C.

When an acidic salt of Compound [56] is used, the reaction may becarried out in the presence of a base including an organic base such astriethylamine; an alkali metal salt such as sodium carbonate; etc.

(Step 7)

Compound [2h] or a salt thereof may be obtained by removing P^(C7) ofCompound [57] by a conventional deprotection reaction. The deprotectionreaction may be carried out using suitable conditions for each of kindsof P^(C7). For example, when P^(C7) is methyl group, Compound [2h] or asalt thereof may be obtained by hydrolyzing Compound [57] in thepresence of a base in a solvent.

The base includes, for example, lithium hydroxide, sodium hydroxide,potassium hydroxide, preferably sodium hydroxide.

A preferable solvent is, for example, an alcoholic solvent such asmethanol; an ether solvent such as tetrahydrofuran; water; or a mixedsolvent thereof.

The reaction temperature is usually about 0 to 100° C., preferably about0 to 40° C.

When Compounds [2h] has an enantiomer thereof, the reaction may becarried out using a commercially available optically active compound orusing a product obtained therefrom by a conventional method.

When Compound [2h] or a salt thereof is used, Compound [Ib] or a saltthereof may be obtained by treating by the same procedure as PreparationMethod 1-3, followed by removing P^(N6) by a conventional deprotectionreaction. The deprotection reaction may be carried out using suitableconditions for each of kinds of P^(N6). For example, when P^(N6) istert-butoxycarbonyl group, Compound [Ib] or a salt thereof may beobtained by the same procedure as Step 2 of Preparation Method 1-2.

EXAMPLES

Preparations of a compound or a pharmaceutically acceptable salt thereofin the present invention are specifically illustrated by Examples.However, the present invention is not intended to be limited thereto.

Stereochemistry in chemical structural formulae of compounds arepartially abbreviated in the Examples.

Measurement apparatuses and conditions used in the Examples are asfollows.

HPLC Analysis Condition 1

Preparation for solvent A: Sodium dihydrogen phosphate dihydrate (2.34g) was dissolved in water (3000 ml) to be adjusted to pH 2.6 by usingphosphoric acid (1.02 ml).Measurement instrument: HPLC system SHIMADZU CORPORATION HighPerformance Liquid Chromatograph ProminenceColumn: DAICEL CHIRALPAK AD-3R 4.6 mmφ×150 mmColumn temperature: 40° C.Mobile phase: (solvent A) 10 mM phosphate (sodium) buffer (pH 2.6),(solvent B) acetonitrile solvent A: solvent B=60:40 constant (12 minutesflow)Flow rate: 0.5 ml/min

Detection: UV (220 nm) HPLC Analysis Condition 2

Preparation for solvent A: Sodium dihydrogenphosphate dihydrate (2.34 g)was dissolved in water (3000 ml), and to be adjusted to pH 2.6 by usingphosphoric acid (1.02 ml).Measurement instrument: HPLC system SHIMADZU CORPORATION HighPerformance Liquid Chromatograph ProminenceColumn: DAICEL CHIRALPAK AD-3R 4.6 mmφ×150 mmColumn temperature: 40° C.Mobile phase: (solvent A) 10 mM phosphate (sodium) buffer (pH 2.6),(solvent B) acetonitrileSolvent A:Solvent B=50:50 constant (12 minutes flow)Flow rate: 0.5 ml/min

Detection: UV (220 nm) HPLC Analysis Condition 3

Measurement instrument: HPLC system SHIMADZU CORPORATION HighPerformance Liquid Chromatograph ProminenceColumn: DAICEL CHIRALCEL OD 4.6 mmφ×250 mmColumn temperature: 40° C.Mobile phase: (solvent A) n-hexane, (solvent B) 2-propanolSolvent A:Solvent B=10:90 constant (30 minutes flow)Flow rate: 0.3 ml/min

Detection: UV (254 nm)

NMR was used with 400 MHz.

[Preparation 1]: Synthesis of 4-methyl-5-oxopyrrolidine-3-carboxylicacid

(1) (Z)-2-Bromomethyl-2-butenedioic acid dimethyl ester

To a solution of (Z)-2-methyl-2-butenedioic acid dimethyl ester (15.3 g)in carbon tetrachloride (300 ml) were added N-bromosuccinimide (25.8 g)and 2,2′-azobis(isobutyronitrile) (319 mg), and the mixture was stirredfor 36 hours at reflux. After cooling the mixture to room temperature,the insoluble substance was filtered off, and the filtrate wasconcentrated. The resulting residue was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=1/0 to 18/1) to give thetitled compound (19.6 g).

¹H-NMR (CDCl₃) δ: 3.83 (s, 3H), 3.88 (s, 3H), 4.72 (s, 2H), 6.84 (s,1H).

(2) 2-Methyl-3-methylenesuccinic acid dimethyl ester

To a solution of (Z)-2-bromomethyl-2-butenedioic acid dimethyl ester(19.3 g) and hexamethylphosphoric acid triamide (70 ml) in diethyl ether(200 ml) was added dropwise methyl magnesium bromide (1.12 M solution intetrahydrofuran, 100 ml) over 1 hour at −20° C. and stirred foradditional 1 hour. To this reaction mixture were added a 6M aqueoussolution of hydrochloric acid (18 ml) and a saturated aqueous solutionof ammonium chloride (100 ml), and then the mixture was warmed to roomtemperature and extracted with diethyl ether (200 ml). The resultingorganic layer was washed with water twice, followed by a saturatedaqueous solution of sodium chloride once, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (eluent:n-hexane/chloroform=1/1 to 0/1) to give the titled compound (9.92 g).

¹H-NMR (CDCl₃) δ: 1.38 (d, 3H, J=7.2 Hz), 3.62 (q, 1H, J=7.2 Hz), 3.69(s, 3H), 3.77 (s, 3H), 5.72 (s, 1H), 6.34 (s, 1H).

(3) Mixture of(cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid methyl ester and(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid methyl ester

To a solution of 2-methyl-3-methylenesuccinic acid dimethyl ester (9.81g) in toluene (100 ml) was added 2,4-dimethoxybenzylamine (9.72 g) andthe mixture was stirred for 3 days at reflux. This reaction solution wascooled to room temperature and then purified by silica gel columnchromatography (eluent: n-hexane/chloroform=1/1 to 0/1) to give thetitled compound (14.2 g).

¹H-NMR (CDCl₃) cis δ: 1.13 (d, 3H, J=7.5 Hz), 2.75-2.86 (m, 1H),3.22-3.34 (m, 2H), 3.48-3.56 (m, 1H), 3.69 (s, 3H), 3.80 (bs, 6H), 4.41(d, 1H, J=14.4 Hz), 4.47 (d, 1H, J=14.4 Hz), 6.42-6.48 (m, 2H),7.13-7.17 (m, 1H). trans δ: 1.30 (d, 3H, J=6.6 Hz), 2.66-2.80 (m, 2H),3.31-3.43 (m, 2H), 3.71 (s, 3H), 3.80 (s, 6H), 4.41 (d, 1H, J=14.4 Hz),4.45 (d, 1H, J=14.4 Hz), 6.41-6.47 (m, 2H), 7.10-7.15 (m, 1H).

(4)(Trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid

To a solution of a mixture of(cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid methyl ester and(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid methyl ester (14.2 g) in methanol (150 ml) was added sodiummethoxide (about 5M solution in methanol, 28 ml), and the mixture wasstirred at room temperature for 16 hours, and then heated to 55° C. andstirred for 3 hours. To this reaction solution was added sodiummethoxide (about 5M solution in methanol, 10 ml), and the mixture wasstirred at 55° C. for additional 2 hours. This reaction solution wascooled to room temperature, and then water (50 ml) was added thereto,and the mixture was stirred overnight. The reaction solution wasconcentrated under reduced pressure to remove methanol. To the resultingresidue was added a 2M aqueous solution of hydrochloric acid (105 ml),and the mixture was extracted with ethyl acetate (300 ml). The resultingorganic layer was washed with a saturated aqueous solution of sodiumchloride, and then dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give a crude product of the titled compound(14.0 g).

¹H-NMR (CDCl₃) δ: 1.32 (d, 3H, J=6.6 Hz), 2.69-2.84 (m, 2H), 3.35-3.46(m, 2H), 3.80 (s, 6H), 4.43 (s, 2H), 6.41-6.47 (m, 2H), 7.10-7.15 (m,1H).

(5) Optically Active compound of(R)-4-benzyl-3-[(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone

To a solution of the crude product of(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid (14.0 g) in chloroform (60 ml) were sequentially added(R)-4-benzyl-2-oxazolidinone (8.15 g), WSC.HCl (9.70 g),4-dimethylaminopyridine (2.81 g), and the mixture was stirred overnightat room temperature. This reaction solution was purified by silica gelcolumn chromatography (eluent: n-hexane/ethyl acetate=4/1 to 1/3) togive the titled compound (low-polarity component 11.4 g, high-polaritycomponent 10.1 g).

¹H-NMR (CDCl₃) low-polarity component δ: 1.31 (d, 3H, J=7.3 Hz),2.77-2.85 (m, 1H), 2.94-3.03 (m, 1H), 3.19-3.30 (m, 2H), 3.51-3.58 (m,1H), 3.79 (s, 3H), 3.80 (s, 3H), 3.96-4.03 (m, 1H), 4.19-4.23 (m, 2H),4.41 (d, 1H, J=15.8 Hz), 4.49 (d, 1H, J=15.8 Hz), 4.63-4.70 (m, 1H),6.42-6.46 (m, 2H), 7.10-7.21 (m, 3H), 7.27-7.37 (m, 3H). high-polaritycomponent δ: 1.26 (d, 3H, J=7.3 Hz), 2.67-2.75 (m, 1H), 2.97-3.08 (m,1H), 3.15-3.24 (m, 1H), 3.63-3.93 (m, 8H), 4.17-4.28 (m, 3H), 4.36-4.56(m, 2H), 4.63-4.73 (m, 1H), 6.39-6.56 (m, 2H), 7.11-7.21 (m, 3H),7.27-7.39 (m, 3H).

(6) Optically Active Compound of(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid

To a solution of lithium hydroxide monohydrate (1.26 g) in water (30 ml)was added dropwise 30 wt % aqueous solution of hydrogen peroxide (7.0ml) under ice-cooling, and the mixture was stirred for 10 minutes. Tothis reaction solution was added tetrahydrofuran 30 ml, and then asolution of the low-polarity component of(R)-4-benzyl-3-[(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone(11.4 g) in tetrahydrofuran (90 ml) was added dropwise thereto, and thenthe mixture was stirred for additional 1 hour. To this reaction solutionwas added dropwise a solution of sodium hydrogen sulfite (7.18 g) inwater (50 ml), and then the mixture was warmed to room temperature, andstirred for 1 hour. This mixture was extracted with ethyl acetate, andthe resulting organic layer was washed with a saturated aqueous solutionof sodium chloride, and then dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluent: chloroform/ethylacetate=1/1 to 1/2, chloroform/methanol=5/1) to give a crude product ofthe titled compound (8.11 g). An analysis of the solid by HPLC analysiscondition 1 showed that an isomer with shorter retention time was a mainproduct.

An isomer with shorter retention time (retention time 5.7 minutes)

An isomer with longer retention time (retention time 6.5 minutes)

Alternatively, the titled compound can be prepared according to thefollowing method.

(6)-(1) Diastereomeric salt of an optically active compound of(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid and (1R,2R)-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol

(Trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid (1.0 g), (1R,2R)-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (434mg), acetonitrile (10 ml) and water (0.9 ml) were mixed, and stirred atreflux to dissolve. This mixed solution was stirred at 50° C. for 6hours, and then stirred at room temperature overnight. A solidprecipitated from this mixed solution was collected by filtration,washed with acetonitrile (6 ml), and dried under reduced pressure togive a solid 1 of the titled compound (572 mg). An analysis of the solid1 by HPLC analysis condition 1 showed that an isomer with shorterretention time was a main product.

An isomer with shorter retention time (retention time 5.7 minutes)

An isomer with longer retention time (retention time 6.5 minutes)

¹H-NMR (DMSO-D₆) δ: 1.11 (d, 3H, J=7.3 Hz), 2.43-2.53 (m, 1H), 2.55-2.64(m, 1H), 2.85-2.92 (m, 1H), 3.14-3.22 (m, 2H), 3.27 (dd, 1H, J=9.3, 9.3Hz), 3.38 (dd, 1H, J=11.3, 4.8 Hz), 3.73 (s, 3H), 3.76 (s, 3H), 4.19 (d,1H, J=14.5 Hz), 4.29 (d, 1H, J=14.5 Hz), 4.73 (d, 1H, J=6.0 Hz), 6.46(dd, 1H, J=8.1, 2.4 Hz), 6.54 (d, 1H, J=2.4 Hz), 6.97 (d, 1H, J=8.1 Hz),7.61 (d, 2H, J=8.5 Hz), 8.19 (d, 2II, J=8.5 Hz).

An X ray crystal structural analysis of the crystal obtained byrecrystallization of the solid 1 from methyl isobutyl ketone showed thatthis crystal was a diastereomeric salt of(3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid and (1R,2R)-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.

(6)-(2)(3R,4R)-1-(2,4-Dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid

A diastereomeric salt of(3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid and (1R,2R)-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (10.0 g)was mixed with ethyl acetate (38 ml), potassium hydrogen sulfate (2.4 g)and water (38 ml), and stirred at room temperature for 30 minutes. Anorganic layer was separated, and a separated aqueous layer was againextracted twice with ethyl acetate (15 ml). The combined organic layerwas washed with a saturated aqueous solution of sodium chloride, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.To the resulting residue were added 2-propanol (2.2 ml) and diisopropylether (45 ml), and the mixture was stirred. The insoluble substance wascollected by filtration, washed with a small amount of diisopropylether, and dried under reduced pressure to give the titled compound (4.3g). An analysis of this solid by HPLC analysis condition 1 showed thatan isomer with shorter retention time was a main product.

An isomer with shorter retention time (retention time 5.7 minutes)

An isomer with longer retention time (retention time 6.5 minutes)

(7) (3R,4R)-4-Methyl-5-oxopyrrolidine-3-carboxylic acid

To a crude product of(3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylicacid (8.11 g) were added anisole (3.76 ml) and trifluoroacetic acid (40ml), and the mixture was stirred at 80° C. for 5 hours. This reactionsolution was cooled to room temperature, and concentrated under reducedpressure. To the resulting residue was added diisopropyl ether, and themixture was stirred. The insoluble substance was collected byfiltration, and dried under reduced pressure to give a crude product ofthe titled compound (2.23 g). To the resulting solid was added ethanol(8 ml), and the mixture was heated at reflux to dissolve, and then thesolution was stirred at room temperature. A solid precipitated from themixed solution was collected by filtration, washed with a small amountof cooled ethanol, and dried under reduced pressure to give the titledcompound (1.36 g).

¹H-NMR (DMSO-D₆) δ: 1.10 (d, 3H, J=7.3 Hz), 2.40 (dq, 1H, J=9.0, 7.3Hz), 2.83 (ddd, 1H, J=9.0, 8.6, 7.6 Hz), 3.22 (dd, 1H, J=10.0, 7.6 Hz),3.37 (dd, 1H, J=10.0, 8.6 Hz), 7.66 (s, 1H), 12.58 (s, 1H).

Also, the high-polarity component of(R)-4-benzyl-3-[(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone(10.1 g) was subjected to the similar reactions and post-treatment asdescribed above to give (3S,4S)-4-methyl-5-oxopyrrolidine-3-carboxylicacid (1.53 g) as the optical isomer of the titled compound.

¹H-NMR (DMSO-D₆) δ: 1.10 (d, 3H, J=7.3 Hz), 2.40 (dq, 1H, J=9.0, 7.3Hz), 2.83 (ddd, 1H, J=9.0, 8.6, 7.6 Hz), 3.22 (dd, 1H, J=10.0, 7.6 Hz),3.37 (dd, 1H, J=10.0, 8.6 Hz), 7.66 (s, 1H), 12.58 (s, 1H).

[Preparation 2]: Example 1: Synthesis of((3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid[1-phenyl-5-(3-trifluoromethoxyphenyl)-1H-pyrazol-3-yl]amide)

(1) 1-Phenyl-1H-pyrazol-3-ylamine

To a solution of 1-phenyl-4,5-dihydro-1H-pyrazol-3-ylamine (50.0 g) inN,N-dimethylformamide (150 ml) and 1,4-dioxane (500 ml) was added3,4,5,6-tetrachloro-1,4-benzoquinone (84.0 g) under ice-cooling over 20minutes, and the mixture was stirred at room temperature for 4.5 hours.To the reaction mixture was added a 2M aqueous solution of sodiumhydroxide (400 ml) under ice-cooling over 25 minutes, and the mixturewas stirred at room temperature for 1 hour. The mixture was filteredthrough Celite to remove the insoluble substance, and eluted with ethylacetate (250 ml×3), and then the filtrate was extracted with ethylacetate (300 ml). The resulting organic layer was sequentially washedwith water (300 ml) and a saturated aqueous solution of sodium chloride(300 ml). The separated aqueous layer was extracted twice with ethylacetate (300 ml). To the combined organic layer were added anhydroussodium sulfate (50 g) and silica gel (50 g), and the mixture was stirredat room temperature for 1 hour. This mixture was filtered with silicagel (100 g) on Celite, and subjected to elution with ethyl acetate (250ml×3). The filtrate was concentrated, and diisopropyl ether (500 ml) wasadded to the resulting residue, and the mixture was stirred at roomtemperature. The insoluble substance was collected by filtration, washedtwice with diisopropyl ether (100 ml), and dried under reduced pressureto give the titled compound (12.2 g).

¹H-NMR (CDCl₃) δ: 3.81 (br s, 2H), 5.85 (d, 1H, J=2.4 Hz), 7.16-7.19 (m,1H), 7.38-7.40 (m, 2H), 7.55-7.57 (m, 2H), 7.69 (d, 1H, J=2.4 Hz).

(2) 3-(2,5-Dimethylpyrrol-1-yl)-1-phenyl-1H-pyrazole

To a solution of 1-phenyl-1H-pyrazol-3-ylamine (32.7 g) in acetic acid(330 ml) was added 2,5-hexanedione (25 ml), and the mixture was stirredfor 3 hours at reflux. This reaction solution was cooled to roomtemperature, and then acetic acid was concentrated under reducedpressure, and then toluene (100 ml) was added thereto, and the mixturewas further concentrated. The resulting residue was purified by silicagel column chromatography (eluent: n-hexane/ethyl acetate 100/1 to 20/1)to give the titled compound (41.8 g).

¹H-NMR (CDCl₃) δ: 2.19 (s, 6H), 5.90 (s, 2H), 6.39 (d, 1H, J=2.4 Hz),7.29-7.31 (m, 1H), 7.46-7.48 (m, 2H), 7.72-7.73 (m, 2H), 7.98 (d, 1H,J=2.4 Hz).

(3) 3-(2,5-Dimethylpyrrol-1-yl)-5-iodo-1-phenyl-1H-pyrazole

To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-phenyl-1H-pyrazole (14.6g) in tetrahydrofuran (80 ml) cooled to −78° C. was added n-butyllithium(1.6M solution in n-hexane, 24 ml) over 5 minutes, and then the mixturewas stirred for 1 hour. To this mixture was added a solution of iodine(15.7 g) in tetrahydrofuran (30 ml) over 10 minutes, and the mixture wasstirred for additional 1.5 hours. To this mixture were sequentiallyadded water (5 ml) and a saturated aqueous solution of sodium hydrogensulfite (30 ml), and then the mixture was warmed to 0° C., andadditional water (150 ml) was added thereto, and the mixture was stirredat room temperature for 1 hour. A precipitated solid was collected byfiltration, washed with water and a small amount of methanol, and driedunder reduced pressure to give the titled compound (13.0 g).

¹H-NMR (CDCl₃) δ: 2.19 (s, 6H), 5.88 (s, 2H), 6.55 (s, 1H), 7.44-7.53(m, 3H), 7.57-7.60 (m, 2H).

(4) 5-Iodo-1-phenyl-1H-pyrazol-3-ylamine

To a solution of 3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1-phenyl-1H-pyrazole(12.2 g) in ethanol/water (2/1,180 ml) were sequentially addedhydroxylammonium chloride (46.6 g) and triethylamine (9.3 ml), and themixture was stirred at 95° C. for 72 hours. This reaction mixture wascooled to room temperature, and concentrated under reduced pressure. Tothe resulting residue was added a 8M aqueous solution of sodiumhydroxide (80 ml), and then the mixture was extracted with ethyl acetate(50 ml). This organic layer was sequentially washed with water and asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate=3/1) to give the titled compound (9.1 g).

¹H-NMR (CDCl₃) δ: 3.77 (br s, 2H), 6.01 (s, 1H), 7.35-7.51 (m, 5H).

(5) 1-Phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine

To a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (605 mg) inethylene glycol dimethyl ether (12 ml) were sequentially added3-(trifluoromethoxy)phenyl boronic acid (481 mg), a 2M aqueous solutionof sodium carbonate (6 ml), tricyclohexylphophine (119 mg), palladiumacetate (48 mg), and the mixture was stirred for 2 hours at reflux. Thisreaction mixture was cooled to room temperature, and a saturated aqueoussolution of sodium hydrogen carbonate was added thereto, and then themixture was filtered through Celite. The filtrate was extracted withethyl acetate. The resulting organic layer was washed with a saturatedaqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (eluent: n-hexane/ethylacetate=2/1) to give the titled compound (298 mg).

¹H-NMR (CDCl₃) δ: 3.79 (br s, 2H), 5.95 (s, 1H), 7.04 (s, 1H), 7.13-7.34(m, 8H).

(6) (3R,4R)-4-Methyl-5-oxopyrrolidine-3-carboxylic acid[1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide

To a solution of1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (79 mg) inN,N-dimethylformamide (0.8 ml) were sequentially added(3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (46 mg) prepared inPreparation 1, HOBt.H₂O (57 mg) and WSC.HCl (71 mg), and the mixture wasstirred at room temperature for 2 hours. To this reaction solution wereadded water and a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. Theseparated organic layer was washed with a saturated aqueous solution ofsodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel thin-layer chromatography (eluent:chloroform/methanol=10/1) to give the titled compound (63 mg).

¹H-NMR (DMSO-D₆) δ: 1.08 (d, 3H, J=7.3 Hz), 2.55 (ddd, 1H, J=9.3, 8.8,8.8 Hz), 3.04 (dq, 1H, J=9.3, 7.3 Hz), 3.23 (dd, 1H, J=8.8, 8.8 Hz),3.45 (dd, 1H, J=8.8, 8.8 Hz), 7.03 (s, 1H), 7.09 (s, 1H), 7.26 (t, 2H,J=6.7 Hz), 7.35-7.45 (m, 5H), 7.52 (t, 1H, J=8.0 Hz), 7.68 (s, 1H),10.99 (s, 1H).

(7) Crystals of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid[1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide

The titled compound was dissolved in ethyl acetate at 90° C., andrecrystallized by an addition of heptane thereto at the same temperatureto give a crystal of the titled compound. Furthermore, the correspondingcrystal as above was suspended in water at 100° C. to give an anothercrystal of the titled compound.

[Preparation 3]: Example 2: Synthesis of((3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid[1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide)

(1) Mixture of (E)-3-(3-(trifluoromethoxy)phenyl)acrylonitrile and(Z)-3-(3-(trifluoromethoxy)phenyl)acrylonitrile

To a suspension of (cyanomethyl) triphenylphosphonium chloride (2.89 g)in tetrahydrofuran (10 ml) was added potassium tert-butoxide (942 mg)under ice-cooling, and the mixture was stirred at room temperature for 1hour. To this reaction solution was added 3-trifluoromethoxybenzaldehyde(1.33 g) under ice-cooling, and then the mixture was stirred at roomtemperature overnight. To this reaction solution was added n-hexane (20ml), and the insoluble substance was filtered off, and then the filtratewas concentrated. The resulting residue was purified by silica gelcolumn chromatography (eluent: n-hexane/ethyl acetate=1/0 to 10/1) togive the titled compound (1.28 g).

¹H-NMR (CDCl₃) (E)-isomer δ: 5.92 (1H, d, J=16.8 Hz), 7.27-7.49 (5H, m).

(Z)-isomer δ: 5.55 (1H, d, J=12.0 Hz), 7.12 (1H, d, J=12.0 Hz),7.35-7.52 (2H, m), 7.60 (1H, s), 7.79 (1H, d, J=8.0 Hz).

(2)1-(4-Fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-3-ylamine

To a solution of a mixture of(E)-3-(3-(trifluoromethoxy)phenyl)acrylonitrile and(Z)-3-(3-(trifluoromethoxy)phenyl)acrylonitrile (1.28 g) in ethanol (13ml) were sequentially added 4-fluorophenylhydrazine hydrochloride (979mg) and sodium ethoxide (20 wt % in ethanol, 5.0 ml), and the mixturewas stirred overnight at reflux. This reaction solution was concentratedunder reduced pressure, and then water was added thereto, and themixture was extracted with ethyl acetate. This organic layer wassequentially washed with water and a saturated aqueous solution ofsodium chloride, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=2/1 to 1/1) to give the titled compound(1.29 g).

¹H-NMR (CDCl₃) δ: 2.79 (dd, 1H, J=16.3, 8.8 Hz), 3.41 (dd, 1H, J=16.3,11.0 Hz), 3.98 (s, 2H), 4.83 (dd, 1H, J=11.0, 8.8 Hz), 6.72-6.87 (m,4H), 7.14 (d, 1H, J=7.9 Hz), 7.25 (s, 1H), 7.32 (d, 1H, J=7.7 Hz), 7.38(dd, 1H, J=7.9, 7.7 Hz).

(3)1-(4-Fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine

To a solution of1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-3-ylamine(1.29 g) in toluene (10 ml) was added activated carbon (pH5 to 8, 0.64g), and the mixture was stirred for 2 hours under oxygen atmosphereunder cooling to reflux. After cooling to room temperature, theactivated carbon was filtered off through Celite eluting with ethylacetate. This filtrate was concentrated under reduced pressure. To theresulting residue, a mixed solvent of diisopropyl ether/n-hexane wasadded and the mixture was stirred at room temperature. The insolublesubstance was collected by filtration, and then dried under reducedpressure to give the titled compound (652 mg).

¹H-NMR (CDCl₃) δ: 3.78 (bs, 1H), 5.95 (s, 1H), 6.97-7.05 (m, 3H),7.13-7.21 (m, 4H), 7.334 (t, 1H, J=8.0 Hz).

(4) (3R,4R)-4-Methyl-5-oxopyrrolidine-3-carboxylic acid[1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide

To a solution of1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine(90 mg) in N,N-dimethylformamide (0.9 ml) were added(3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (50 mg) prepared inPreparation 1, HOBt.H₂O (61 mg) and WSC.HCl (77 mg), and the mixture wasstirred at room temperature for 2 hours. To this mixture were addedwater and a saturated aqueous solution of sodium hydrogen carbonate, andthe mixture was extracted with ethyl acetate. The separated organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=10/1) to give the titledcompound (80 mg).

1H-NMR (DMSO-D6) δ: 1.08 (d, 3H, J=7.1 Hz), 2.54 (dq, 1H, J=9.3, 7.1Hz), 3.04 (ddd, 1H, J=9.3, 9.2, 8.4 Hz), 3.23 (dd, 1H, J=9.2, 8.6 Hz),3.44 (dd, 1H, J=8.6, 8.4 Hz), 7.03 (s, 1H), 7.11 (s, 1H), 7.25-7.38 (m,6H), 7.53 (dd, 1H, J=8.2, 7.9 Hz), 7.68 (s, 1H), 10.98 (s, 1H).

[Preparation 4]: Example 3: Synthesis of((3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid[1-(3-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide)

(1) 3-(2,5-Dimethylpyrrol-1-yl)-1H-pyrazole

To a solution of 3-aminopyrazole (100 g) in acetic acid (1000 ml) wasadded 2,5-hexanedione (148 ml), and the mixture was stirred for 2.4hours at reflux. This reaction solution was cooled to room temperature,water (1000 ml) was added thereto, and the precipitated solid wascollected by filtration. The resulting solid was washed with water (1000ml), and dried under reduced pressure to give the titled compound (183g).

¹H-NMR (DMSO-D₆) δ: 2.00 (s, 6H), 5.74 (s, 2H), 6.27 (d, 1H, J=2.1 Hz),7.84 (d, 1H, J=2.1 Hz), 12.90 (s, 1H).

(2) 3-(2,5-Dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-1H-pyrazole

To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (6.8 g) inN-methyl-2-pyrrolidone (68 ml) were sequentially added cesium carbonate(27.4 g), 8-quinolinol (1.2 g), copper oxide (I) (0.6 g) and1-fluoro-3-iodobenzene (7.4 mil), and the mixture was stirred at 110° C.for 2 hours. This reaction mixture was cooled to room temperature, andtoluene (80 ml) was added thereto, and then the mixture was filteredthrough Celite. After adding a 1M aqueous solution of sodium hydroxide(80 ml) to the filtrate, the mixture was extracted with toluene. Theresulting organic layer was sequentially washed with water and asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate=9/1) to give the titled compound (10.4 g).

¹H-NMR (CDCl₃) δ: 2.19 (s, 6H), 5.90 (s, 2H), 6.41 (d, 1H, J=2.6 Hz),6.97-7.02 (m, 1H), 7.39-7.45 (m, 1H), 7.48-7.49 (m, 1H), 7.49-7.52 (m,1H), 7.97 (d, 1H, J=2.6 Hz).

(3) 3-(2,5-Dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-5-iodo-1H-pyrazole

To a solution of3-(2,5-dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-1H-pyrazole (10.4 g) intetrahydrofuran (100 ml) cooled to −78° C. was added n-butyllithium(1.6M solution in n-hexane, 31 ml) over 10 minutes, and then the mixturewas stirred for 30 minutes. To the mixture was added dropwise a solutionof iodine (12.4 g) in tetrahydrofuran (20 ml) over 10 minutes, and themixture was stirred for additional 30 minutes. To the mixture weresequentially added a 20 wt % aqueous solution of sodium thiosulfate anda saturated aqueous ammonia, and then the mixture was warmed to roomtemperature, and extracted with ethyl acetate. The separated organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. To the resulting residue was added a mixed solvent ofn-hexane/ethyl acetate (2/1), and the mixture was stirred. The insolublesubstance was collected by filtration, and dried under reduced pressureto give the titled compound (4.5 g).

¹H-NMR (CDCl₃) δ: 2.19 (s, 6H), 5.88 (s, 2H), 6.56 (s, 1H), 7.15-7.19(m, 1H), 7.35-7.37 (m, 1H), 7.41-7.50 (m, 2H).

(4) 1-(3-Fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine

To a solution of3-(2,5-dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-5-iodo-1H-pyrazole (4.5g) in ethanol/water (2/1, 81 ml) were sequentially addedhydroxylammonium chloride (16.3 g) and triethylamine (3.3 ml), and themixture was stirred at 95° C. for 17 hours. This reaction mixture wascooled to room temperature and concentrated under reduced pressure. Tothe resulting residue was added an 8M aqueous solution of sodiumhydroxide, and the mixture was extracted with ethyl acetate. Thisorganic layer was sequentially washed with water and a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1)to give the titled compound (3.2 g).

¹H-NMR (CDCl₃) δ: 3.78 (br s, 2H), 6.03 (s, 1H), 7.05-7.09 (m, 1H),7.26-7.29 (m, 1H), 7.32-7.43 (m, 2H).

(5)1-(3-Fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine

To a solution of 1-(3-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (263 mg)in ethylene glycol dimethyl ether (5 ml) were sequentially added3-(trifluoromethoxy)phenylboronic acid (197 mg), a 2M aqueous solutionof sodium carbonate (2.5 ml), tricyclohexylphosphine (49 mg), palladiumacetate (20 mg), and the mixture was stirred for 2 hours at reflux. Thisreaction mixture was cooled to room temperature, a saturated aqueoussolution of sodium hydrogen carbonate was added thereto; and then themixture was filtered through Celite. The filtrate was extracted withethyl acetate, the resulting organic layer was washed with a saturatedaqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (eluent: n-hexane/ethylacetate=2/1) to give the titled compound (234 mg).

¹H-NMR (CDCl₃) δ: 3.82 (br s, 2H), 5.96 (s, 1H), 6.92-7.02 (m, 3H),7.05-7.07 (m, 1H), 7.17-7.38 (m, 4H).

(6) (3R,4R)-4-Methyl-5-oxopyrrolidine-3-carboxylic acid[1-(3-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide

To a solution of1-(3-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine(68 mg) in N,N-dimethylformamide (0.7 ml) were sequentially added(3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (38 mg) prepared inPreparation 1, HOBt.H₂O (46 mg) and WSC.HCl (58 mg), and the mixture wasstirred at room temperature for 2 hours. To this reaction solution wereadded water and a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. Theseparated organic layer was washed with a saturated aqueous solution ofsodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel thin-layer chromatography (eluent:chloroform/methanol=10/1) to give the titled compound (33 mg).

¹H-NMR (DMSO-D₆) δ:1.08 (d, 3H, J=7.3 Hz), 2.54 (dq, 1H, J=9.3, 7.3 Hz),3.04 (ddd, 1H, J=9.3, 8.9, 8.5 Hz), 3.23 (dd, 1H, J=8.9, 8.7 Hz), 3.45(dd, 1H, J=8.7, 8.5 Hz), 7.04 (s, 1H), 7.05-7.07 (m, 1H), 7.14-7.18 (m,2H), 7.22-7.26 (m, 1H), 7.39-7.48 (m, 3H), 7.56 (t, 1H, J=8.0 Hz), 7.68(s, 1H), 11.03 (s, 1H).

[Preparation 5]: Synthesis of (R) and (S)-5-oxopyrrolidine-3-carboxylicacid

(1) 1-(2,4-Dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid

To a solution of itaconic acid (65.3 g) in toluene (400 ml) was added asolution of 2,4-dimethoxybenzylamine (84.0 g) in toluene (100 ml), andthe mixture was stirred for 15 hours at reflux. This reaction solutionwas cooled to room temperature, and concentrated under reduced pressure.To the resulting residue was added diethyl ether (600 ml), and themixture was stirred. The precipitated solid was collected by filtration,washed with diethyl ether and a small amount of ethyl acetate, and thendried under reduced pressure to give the titled compound (127 g).

¹H-NMR (CDCl₃) δ: 2.66-2.82 (m, 2H), 3.20 (dt, 1H, J=17.3, 7.6 Hz),3.49-3.53 (m, 2H), 3.80 (s, 6H), 4.40 (d, 1H, J=14.6 Hz), 4.46 (d, 1H,J=14.6 Hz), 6.42-6.47 (m, 2H), 7.14 (t, 1H, J=4.5 Hz).

(2) Optically Active Compound of(R)-4-benzyl-3-[1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone

To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylicacid (31.7 g) in chloroform (300 ml) were sequentially added(R)-4-benzyl-2-oxazolidinone (20.0 g), WSC.HCl (23.8 g) and4-dimethylaminopyridine (6.90 g) under ice-cooling, the mixture wasstirred for 15 minutes, warmed to room temperature and stirred for 18hours. This reaction mixture was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=1/1 to 1/9) to give thetitled compound (low-polarity component 26.4 g, high-polarity component13.3 g).

¹H-NMR (CDCl₃) low-polarity component δ: 2.72-2.83 (m, 3H), 3.27 (dd,1H, J=13.4, 3.5 Hz), 3.46-3.57 (m, 2H), 3.80 (s, 3H), 3.80 (s, 3H),4.15-4.29 (m, 3H), 4.40-4.48 (m, 2H), 4.61-4.69 (m, 1H), 6.42-6.47 (m,2H), 7.12-7.21 (m, 3H), 7.27-7.37 (m, 3H). high-polarity component δ:2.62-2.72 (m, 2H), 2.86 (dd, 1H, J=16.9, 5.8 Hz), 3.17 (dd, 1H, J=13.4,3.2 Hz), 3.40 (dd, 1H, J=10.4, 5.1 Hz), 3.66 (dd, 1H, J=10.4, 8.8 Hz),3.72 (s, 3H), 3.81 (s, 3H), 4.16-4.26 (m, 3H), 4.40 (d, 1H, J=14.6 Hz),4.50 (d, 1H, J=14.6 Hz), 4.61-4.69 (m, 1H), 6.40-6.45 (m, 2H), 7.11-7.17(m, 3H), 7.27-7.34 (m, 3H).

(3) Optically Active Compound of1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid

To a solution of lithium hydroxide monohydrate (3.29 g) in water (50 ml)was added dropwise 30 wt % aqueous solution of hydrogen peroxide (17.5ml) under cooling with an ice-sodium chloride bath, and the mixture wasstirred for 15 minutes. To this reaction solution was addedtetrahydrofuran (30 ml), and then a solution of the low-polaritycomponent of(R)-4-benzyl-3-[1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone(26.4 g) in tetrahydrofuran (150 ml) was added dropwise thereto, and themixture was stirred for additional 1 hour. To this reaction solution wasslowly added a solution of sodium hydrogen sulfite (18.7 g) in water (60ml), and the mixture was warmed to room temperature by removing thebath, and then extracted with ethyl acetate (100 ml). The resultingorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent: chloroform/ethyl acetate=1/1 to 1/2,chloroform/methanol=5/1) to give the titled compound (14.3 g). Ananalysis of this solid by HPLC analysis condition 2 showed that anisomer with shorter retention time was a main product.

An isomer with shorter retention time (retention time 4.1 minutes)

An isomer with longer retention time (retention time 4.6 minutes)

¹H-NMR (CDCl₃) δ: 2.66-2.82 (m, 2H), 3.20 (dt, 1H, J=17.3, 7.6 Hz),3.49-3.53 (m, 2H), 3.80 (s, 6H), 4.40 (d, 1H, J=14.6 Hz), 4.46 (d, 1H,J=14.6 Hz), 6.42-6.47 (m, 2H), 7.14 (t, 1H, J=4.5 Hz).

(4) Optically Active Compound of 5-oxopyrrolidine-3-carboxylic acid

To an optically active compound of1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (14.3 g) wereadded anisole (8.4 ml) and trifluoroacetic acid (100 ml), and themixture was stirred at 80° C. for 5 hours. This reaction solution wascooled to room temperature, and concentrated under reduced pressure. Tothe resulting residue was added diisopropyl ether (100 ml), and themixture was stirred at room temperature. The insoluble substance wascollected by filtration, washed with diisopropyl ether, and dried underreduced pressure to give the titled compound (4.96 g).

¹H-NMR (DMSO-D₆) δ: 2.26-2.40 (m, 2H), 3.18-3.28 (m, 1H), 3.30-3.35 (m,1H), 3.40-3.47 (m, 1H), 7.64 (s, 1H), 12.58 (s, 1H); [α]_(D) ²⁵ +37 (c0.10, CH₃OH).

It was shown that the resulting compound was(R)-5-oxopyrrolidine-3-carboxylic acid by comparing a specific rotationof the compound with those described in the literature (Tetrahedron:Asymmetry 12 (2001) 3241-3249).

Also, the high-polarity component of(R)-4-benzyl-3-[1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinonewas subjected to the same reactions and post-treatment as describedabove to give (S)-5-oxopyrrolidine-3-carboxylic acid (2.83 g) as theoptical isomer.

¹H-NMR (DMSO-D₆) δ: 2.26-2.40 (m, 2H), 3.18-3.28 (m, 1H), 3.30-3.35 (m,1H), 3.40-3.47 (m, 1H), 7.64 (s, 1H), 12.58 (s, 1H); [α]_(D) ²⁵ −40 (c0.10, CH₃OH).

[Preparation 6]: Example 4: Synthesis of((R)-5-oxopyrrolidine-3-carboxylic acid[1-phenyl-5-(3-trifluoromethoxyphenyl)-1H-pyrazol-3-yl]amide)

(1) (R)-5-Oxopyrrolidine-3-carboxylic acid[1-phenyl-5-(3-trifluoromethoxyphenyl)-1H-pyrazol-3-yl]amide

To a solution of1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (40 mg)prepared according to the same procedures as Preparation 2 inN,N-dimethylformamide (0.3 ml) were sequentially added(R)-5-oxopyrrolidine-3-carboxylic acid (24 mg) prepared in Preparation5, HOBt.H₂O (29 mg) and WSC.HCl (36 mg), and the mixture was stirred atroom temperature overnight. To this reaction solution were added asaturated aqueous solution of sodium hydrogen carbonate and water, andthe mixture was stirred. The insoluble substance was collected byfiltration, washed with water, and dried under reduced pressure to givethe titled compound (45 mg).

¹H-NMR (DMSO-D₆) δ: 2.35-2.42 (m, 2H), 3.31-3.54 (m, 3H), 7.01 (s, 1H),7.08 (s, 1H), 7.22-7.28 (m, 2H), 7.32-7.46 (m, 5H), 7.52 (t, 1H, J=8.0Hz), 7.64 (s, 1H), 10.90 (s, 1H).

[Preparation 7]: Synthesis of Optically Active Compound of6-oxopiperidine-3-carboxylic acid

(1) 2-Methylenepentanedioic acid dimethyl ester

To a solution of2,8,9-triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo(3,3,3) indecane(4.62 g) in tetrahydrofuran (180 ml) was added dropwise a solution ofmethyl acrylate (40.5 ml) in tetrahydrofuran (20 ml) at roomtemperature, and then the mixture was stirred overnight. This reactionsolution was concentrated under reduced pressure, and then diisopropylether, n-hexane and chloroform were added to the resulting residue, andthe mixture was again concentrated under reduced pressure. To theprecipitated solid was added diisopropyl ether, the mixture was stirred,and then the insoluble substance was filtered off. The filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (eluent: n-hexane/ethylacetate=9/1 to 4/1) to give the titled compound (19.2 g).

¹H-NMR (CDCl₃) δ: 2.53 (td, 2H, J=7.6, 1.3 Hz), 2.65 (t, 2H, J=7.6 Hz),3.67 (s, 3H), 3.76 (s, 3H), 5.61 (q, 1H, J=1.3 Hz), 6.20 (d, 1H, J=1.3Hz).

(2) 1-(2,4-Dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid methylester

To a solution of 2-methylenepentanedioic acid dimethyl ester (19.2 g) intoluene (195 ml) was added 2,4-dimethoxybenzylamine (16.6 ml), and themixture was stirred for 3 days at reflux. This reaction solution wascooled to room temperature, and then washed with a 1M aqueous solutionof hydrochloric acid, water and a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give a crude product of the titled compound (26.8g).

¹H-NMR (CDCl₃) δ: 1.93-2.05 (m, 1H), 2.08-2.17 (m, 1H), 2.40-2.50 (m,1H), 2.52-2.62 (m, 1H), 2.74-2.83 (m, 1H), 3.45 (d, 2H, J=7.4 Hz), 3.68(s, 3H), 3.81 (s, 3H), 3.81 (s, 3H), 4.54 (d, 1H, J=14.6 Hz), 4.62 (d,1H, J=14.6 Hz), 6.44-6.48 (m, 2H), 7.15-7.19 (m, 1H).

(3) 1-(2,4-Dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid

To a solution of the crude product of1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid methyl ester(26.8 g) in methanol/tetrahydrofuran (1/1, 174 ml) was added a 1Maqueous solution of sodium hydroxide (174 ml) at room temperature, andthe mixture was stirred overnight. To this reaction solution was added a1M aqueous solution of hydrochloric acid (174 ml), the mixture wasstirred. The precipitated solid was collected by filtration, washed withwater, and dried under reduced pressure to give the titled compound(15.1 g).

¹H-NMR (DMSO-D₆) δ: 1.77-1.90 (m, 1H), 1.95-2.06 (m, 1H), 2.25-2.41 (m,2H), 2.75-2.86 (m, 1H), 3.31 (d, 2H, J=7.1 Hz), 3.74 (s, 3H), 3.78 (s,3H), 4.34 (d, 1H, J=15.2 Hz), 4.43 (d, 1H, J=15.2 Hz), 6.47 (dd, 1H,J=8.4, 2.4 Hz), 6.56 (d, 1H, J=2.4 Hz), 7.00 (d, 1H, J=8.4 Hz), 12.56(br s, 1H).

(4) Optically Active Compound of5-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one

To a solution of 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylicacid (3.39 g) in chloroform (15 ml) were sequentially added(R)-4-benzyl-2-oxazolidinone (2.04 g), WSC.HCl (2.44 g) and4-dimethylaminopyridine (706 mg) at room temperature, and the mixturewas stirred overnight. This reaction mixture was purified by silica gelcolumn chromatography (eluent: chloroform/ethyl acetate=4/1 to 1/1) togive the titled compound (low-polarity component 3.37 g, high-polaritycomponent 2.72 g).

¹H-NMR (CDCl₃) low-polarity component δ: 1.91-2.02 (m, 1H), 2.14-2.24(m, 1H), 2.50-2.66 (m, 2H), 2.73-2.81 (m, 1H), 3.18-3.25 (m, 1H),3.34-3.41 (m, 1H), 3.51-3.60 (m, 1H), 3.78 (s, 3H), 3.80 (s, 3H),3.84-3.93 (m, 1H), 4.05-4.20 (m, 2H), 4.53-4.65 (m, 3H), 6.42-6.47 (m,2H), 7.14-7.38 (m, 6H). high-polarity component ¹H-NMR (CDCl₃) δ:1.92-2.14 (m, 2H), 2.47-2.67 (m, 3H), 3.14-3.23 (m, 1H), 3.44-3.59 (m,2H), 3.77 (s, 3H), 3.81 (s, 3H), 3.91-4.01 (m, 1H), 4.14-4.26 (m, 2H),4.54-4.68 (m, 3H), 6.42-6.49 (m, 2H), 7.15-7.21 (m, 3H), 7.25-7.35 (m,3H).

(5) Optically Active Compound of1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid

To a solution of lithium hydroxide monohydrate (316 mg) in water (10 ml)was added dropwise a 30 wt % aqueous solution of hydrogen peroxide (1.8ml) under ice-cooling and the mixture was stirred for 10 minutes. Tothis reaction solution was added tetrahydrofuran (10 ml), and then asolution of the low-polarity component of5-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one(3.37 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and themixture was stirred for additional 1 hour. To this reaction solution wasadded an aqueous solution of sodium hydrogen sulfite (1.81 g) was addeddropwise, and then the mixture was warmed to room temperature, andstirred for 30 minutes. This mixed solution was extracted with ethylacetate, and the resulting organic layer was washed with a saturatedaqueous solution of sodium chloride, and then dried over anhydroussodium sulfate, and concentrated under reduced pressure. To theresulting residue was added ethyl acetate, and the mixture was stirredat room temperature. The insoluble substance was collected byfiltration, and dried under reduced pressure to give the titled compound(1.36 g). An analysis of this solid by HPLC analysis condition 2 showedthat an isomer with shorter retention time was a main product.

An isomer with shorter retention time (retention time 4.5 minutes) Anisomer with longer retention time (retention time 6.6 minutes)

(6) Optically Active Compound of 6-oxopiperidine-3-carboxylic acid

To an optically active compound of1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid (1.36 g) wereadded anisole (758 μl) and trifluoroacetic acid (10 ml), and the mixturewas stirred at 80° C. for 6 hours. This reaction solution was cooled toroom temperature, and then concentrated under reduced pressure. To theresulting residue was added diisopropyl ether, and the mixture wasstirred at room temperature. The insoluble substance was collected byfiltration, and dried under reduced pressure to give the titled compound(628 mg).

¹H-NMR (DMSO-D₆) δ: 1.75-1.88 (m, 1H), 1.91-2.01 (m, 1H), 2.11-2.24 (m,2H), 2.66-2.73 (m, 1H), 3.21-3.32 (m, 2H), 7.45 (s, 1H), 12.51 (br s,1H).

Also, the high-polarity component of5-((R)-4-benzyl-2-oxoxazolidinone-3-carbonyl)-1-(2,4-dimethoxybenzyl)piperidin-2-onwas subjected to the same reactions and post-treatment as describedabove to give an optical isomer of the titled compound (485 mg).

¹H-NMR (DMSO-D₆) δ: 1.75-1.88 (m, 1H), 1.91-2.01 (m, 1H), 2.11-2.24 (m,2H), 2.66-2.73 (m, 1H), 3.21-3.32 (m, 2H), 7.45 (s, 1H), 12.51 (br s,1H).

[Preparation 8]: Example 5: Synthesis of optically active compound of(6-oxopiperidine-3-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide)

(1) 1-Bromo-3-propylbenzene

To a solution of 3-bromopropiophenone (25 g) in trifluoroacetic acid(250 ml) was added dropwise triethylsilane (94 ml) under ice-coolingover 20 minutes, and the mixture was stirred for additional 20 minutes.This reaction solution was heated to 80° C., and stirred overnight. Thisreaction solution was cooled to room temperature, concentrated underreduced pressure, and again concentrated under reduced pressure afteradding toluene thereto. The resulting residue was purified by silica gelcolumn chromatography (eluent: n-hexane) to give the titled compound(16.6 g).

¹H-NMR (CDCl₃) δ: 0.95 (t, 3H, J=7.4 Hz), 1.64 (tq, 2H, J=7.7, 7.4 Hz),2.57 (t, 2H, J=7.7 Hz), 7.08-7.13 (m, 1H), 7.13-7.18 (m, 1H), 7.30-7.35(m, 2H).

(2) 3-Propylbenzaldehyde

To a solution of 1-bromo-3-propylbenzene (16.6 g) in tetrahydrofuran (83ml) cooled to −78° C. was added dropwise n-butyllithium (2.66M solutionin n-hexane, 34 ml) over 9 minutes, and then the mixture was stirred for1 hour. To this reaction solution was added dropwiseN,N-dimethylformamide (7.7 ml) over 6 minutes, and the mixture wasstirred for additional 20 minutes. To this reaction solution was addeddropwise a 4M solution of hydrogen chloride in 1,4-dioxane (23 ml) over5 minutes, and then the mixture was stirred after warming to roomtemperature. To this mixed solution was added water (83 ml), followed bya 6M aqueous solution of hydrochloric acid (12 ml), and then the mixturewas extracted with n-hexane (80 ml). The resulting organic layer waswashed with a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive a crude product of the titled compound (14.0 g).

¹H-NMR (CDCl₃) δ: 0.95 (t, 3H, J=7.3 Hz), 1.68 (tq, 2H, J=7.7, 7.3 Hz),2.67 (t, 2H, J=7.7 Hz), 7.42-7.47 (m, 2H), 7.67-7.72 (m, 2H), 9.98-10.01(m, 1H).

(3) Mixture of (E)-3-(3-propylphenyl)acrylonitrile and(Z)-3-(3-propylphenyl)acrylonitrile

To a suspension of (cyanomethyl)triphenylphosphonium chloride (34 g) intetrahydrofuran (110 ml) was added portionwise potassium tert-butoxide(13 g) under ice-cooling, and then the mixture was stirred for 1 hour.To this reaction solution was added dropwise a solution of a crudeproduct of 3-propyl benzaldehyde (14.0 g) in tetrahydrofuran (30 ml)over 7 minutes under ice-cooling, and then the mixture was stirred atroom temperature overnight. To this mixture was added n-hexane (280 ml),and the mixture was stirred for 1 hour under ice-cooling, and then theinsoluble substance was filtered off through Celite, and eluted withn-hexane (840 ml). To the resulting residue by concentrating thefiltrate was added a mixed solvent of n-hexane/ethyl acetate (5/1, 120ml), and the mixture was stirred. The insoluble substance was filteredoff through Celite, and eluted with a mixed solvent of n-hexane/ethylacetate (10/1). The filtrate was concentrated, and the resulting residuewas purified by silica gel column chromatography (eluent: n-hexane/ethylacetate=1/0 to 25/1) to give the titled compound (11.4 g).

¹H-NMR (CDCl₃) (E)-isomer δ: 0.95 (t, 3H, J=7.5 Hz), 1.65 (tq, 2H,J=7.7, 7.5 Hz), 2.60 (t, 2H, J=7.7 Hz), 5.87 (d, 1H, J=16.5 Hz),7.22-7.41 (m, 5H). (Z)-isomer δ: 0.95 (t, 3H, J=7.5 Hz), 1.67 (tq, 2H,J=7.7, 7.5 Hz), 2.64 (t, 2H, J=7.7 Hz), 5.42 (d, 1H, J=12.1 Hz), 7.11(d, 1H, J=12.1 Hz), 7.23-7.42 (m, 2H), 7.58-7.66 (m, 2H).

(4) 1-Phenyl-5-(3-propylphenyl)-4,5-dihydro-1H-pyrazol-3-ylamine

To a solution of sodium ethoxide (20 wt % in ethanol, 31 ml) in ethanol(66 ml) was stirred and added dropwise phenylhydrazine (6.4 ml) at roomtemperature, and then the mixture was stirred for 40 minutes. To thisreaction solution was added dropwise a solution of the mixture of(E)-3-(3-propylphenyl)acrylonitrile and(Z)-3-(3-propylphenyl)acrylonitrile (11.1 g) in ethanol (33 ml), andthen the mixture was stirred overnight at reflux. This reaction solutionwas cooled to room temperature, and water (30 ml) was added thereto.Next, pH of the reaction solution was adjusted to 7 by adding a 6Maqueous solution of hydrochloric acid under ice-cooling. This mixedsolution was extracted with ethyl acetate, and the resulting organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. To the resulting residue was added toluene, and the mixturewas dried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. To the resulting residue was added toluene, and againconcentrated under reduced pressure to give a crude product of thetitled compound (18.6 g).

¹H-NMR (CDCl₃) δ: 0.91 (t, 3H, J=7.5 Hz), 1.61 (tq, 2H, J=7.7, 7.5 Hz),2.56 (t, 2H, J=7.7 Hz), 2.78 (dd, 1H, J=16.3, 8.5 Hz), 3.41 (dd, 1H,J=16.3, 11.3 Hz), 3.96 (s, 2H), 4.90 (dd, 1H, J=11.3, 8.5 Hz), 6.67 6.72(m, 1H), 6.80-6.87 (m, 2H), 7.02-7.37 (m, 6H).

(5) 1-Phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine

To a solution of the crude product of1-phenyl-5-(3-propylphenyl)-4,5-dihydro-1H-pyrazol-3-ylamine (18.6 g) intoluene (185 ml) was added activated carbon (pH5 to 8, 9.29 g), and themixture was stirred overnight under oxygen atmosphere at reflux. Thisreaction solution was cooled to room temperature, and then the activatedcarbon was filtered off through Celite, and eluted with ethyl acetate.This filtrate was concentrated under reduced pressure, the resultingresidue was dissolved in toluene (185 ml), and to the solution was addedfresh activated carbon (pH5 to 8, 9.29 g), and the mixture was stirredovernight under oxygen atmosphere at reflux. This reaction solution wascooled to room temperature, and then the activated carbon was filteredoff through Celite, and eluted with ethyl acetate. This filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (eluent: n-hexane/ethylacetate=4/1 to 1/1) to give the titled compound (8.68 g).

¹H-NMR (CDCl₃) δ: 0.82 (t, 3H, J=7.3 Hz), 1.49 (tq, 2H, J=7.6, 7.3 Hz),2.47 (t, 2H, J=7.6 Hz), 3.75 (s, 2H), 5.90 (s, 1H), 6.96-7.00 (m, 1H),7.02-7.12 (m, 2H), 7.15-7.30 (m, 6H).

(6) Optically Active Compound of 6-oxopiperidine-3-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide

To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (56mg) in tetrahydrofuran (1.5 ml) were sequentially added an opticallyactive compound of 6-oxopiperidine-3-carboxylic acid (43 mg) synthesizedin Preparation 7 (derived from the low-polarity component of5-((R)-4-benzyl-2-oxoxazolidine-3-carbonyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one),HOBt.H₂O (46 mg) and WSC.HCl (58 mg), and the mixture was stirred atroom temperature overnight. To this reaction solution was added asaturated aqueous solution of sodium hydrogen carbonate, and the mixturewas extracted with ethyl acetate. The separated organic layer wasconcentrated under reduced pressure, the resulting residue was purifiedby silica gel thin-layer chromatography (eluent:chloroform/methanol=10/1) to give the titled compound (50 mg).

¹H-NMR (DMSO-D₆) δ: 0.77 (t, 3H, J=7.3 Hz), 1.44 (tq, 2H, J=7.5, 7.3Hz), 1.83-2.03 (m, 2H), 2.12-2.30 (m, 2H), 2.46 (t, 2H, J=7.5 Hz), 2.84(tt, 1H, J=10.7, 3.6 Hz), 3.24-3.31 (m, 2H), 6.89 (s, 1H), 7.00 (s, 1H),7.06 (d, 1H, J=7.7 Hz), 7.17 (d, 1H, J=7.7 Hz), 7.19-7.43 (m, 6H), 7.51(s, 1H), 10.83 (s, 1H).

[Preparation 9]: Synthesis of(R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid and(S)-3-methyl-2-oxoimidazolidine-4-carboxylic acid

(1) (R)-2-Oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester

To a solution of sodium hydroxide (743 mg) in water (15 ml) was addeddropwise bromine (318 μl) under ice-cooling over 30 minutes. To thisreaction solution was added Z-D-asparagine (1.5 g), and then the mixturewas heated to 55° C., and stirred for 3 hours. This reaction solutionwas cooled to room temperature, and washed twice with diethyl ether (15ml). To the resulting aqueous layer was added dropwise a 6M aqueoussolution of hydrochloric acid until the pH reached 1. This mixedsolution was left to stand at 4° C. overnight. The precipitated solidwas collected by filtration, washed with water, and dried under reducedpressure to give the titled compound (1.1 g).

¹H-NMR (DMSO-D₆) δ: 3.22 (dd, 1H, J=10.0, 3.3 Hz), 3.65 (dd, 1H, J=10.0,10.2 Hz), 4.68 (dd, 1H, J=10.2, 3.3 Hz), 5.16 (d, 1H, J=14.8 Hz), 5.19(d, 1H, J=14.8 Hz), 7.29-7.39 (m, 5H), 7.57 (s, 1H), 13.25 (br s, 1H).

(2) (R)-2-Oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester5-tert-butyl ester

To a solution of (R)-2-oxoimidazolidine-1,5-dicarboxylic acid 1-benzylester (534 mg) in chloroform (2.6 ml) were sequentially added pyridine(1.0 ml) and tert-butylalcohol (1.5 ml) at room temperature, and themixture was stirred. This reaction solution was iced, and phosphorousoxychloride (0.23 ml) was added thereto, and then the mixture wasstirred at room temperature for 5 hours. This reaction solution wasiced, and a 20 wt % aqueous solution of sodium acetate (20 ml) was addedthereto, and then chloroform (5 ml) was further added at roomtemperature, and the mixture was stirred for 30 minutes. This mixedsolution was extracted with chloroform, and the resulting organic layerwas washed with a 0.1M aqueous solution of hydrochloric acid, water, asaturated aqueous solution of sodium hydrogen carbonate and a saturatedaqueous solution of sodium chloride, and then dried over anhydroussodium sulfate, and concentrated under reduced pressure to give a crudeproduct of the titled compound (467 mg).

¹H-NMR (CDCl₃) δ: 1.39 (s, 9H), 3.38 (dd, 1H, J=9.8, 3.3 Hz), 3.71 (dd,1H, J=9.8, 9.8 Hz), 4.62 (dd, 1H, J=9.8, 3.3 Hz), 5.24 (d, 1H, J=12.6Hz), 5.29 (d, 1H, J=12.6 Hz), 6.00 (br s, 1H), 7.28-7.41 (m, 5H).

(3) (R)-3-Methyl-2-oxoimidazolidine-1,4-dicarboxylic acid 1-benzyl ester4-tert-butyl ester

To a solution of the crude product of(R)-2-oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester 5-tert-butylester (318 mg) in N,N-dimethylformamide (3 ml) was added sodium hydride(42 mg) under ice-cooling, and the mixture was stirred for 40 minutes.To this reaction solution was added methyl iodide (309 μl), and then themixture was warmed to room temperature, and stirred for 4 hours. Thisreaction solution was iced, and water and ethyl acetate were addedthereto, and the mixture was stirred. This mixed solution was extractedwith ethyl acetate, and the resulting organic layer was washed with asaturated aqueous solution of sodium chloride, and then dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (167mg).

¹H-NMR (CDCl₃) δ: 1.48 (s, 9H), 2.91 (s, 3H), 3.81-3.85 (m, 1H),3.96-4.02 (m, 2H), 5.27 (d, 1H, J=13.1 Hz), 5.30 (d, 1II, J=13.1 Hz),7.29-7.45 (m, 5H).

(4) (R)-3-Methyl-2-oxoimidazolidine-4-carboxylic acid tert-butyl ester

To a solution of (R)-3-methyl-2-oxoimidazolidine-1,4-dicarboxylic acid1-benzyl ester 4-tert-butyl ester (167 mg) in methanol (1.7 ml) wasadded 10 wt % palladium on carbon at room temperature, and the mixturewas stirred for 15 hours under one atom of hydrogen. Under nitrogenatmosphere, this reaction solution was filtered through Celite, andeluted with methanol. The filtrate was concentrated under reducedpressure to give the titled compound (94 mg).

¹H-NMR (CDCl₃) δ: 1.50 (s, 9H), 2.86 (s, 3H), 3.41-3.46 (m, 1H),3.62-3.67 (m, 1H), 4.05 (dd, 1H, J=9.8, 6.1 Hz), 4.38 (br s, 1H).

(5) (R)-3-Methyl-2-oxoimidazolidine-4-carboxylic acid

To a solution of (R)-3-methyl-2-oxoimidazolidine-4-carboxylic acidtert-butyl ester (94 mg) in chloroform (2 ml) was added trifluoroaceticacid (1 ml) at room temperature, and the mixture was stirred for 3hours. This reaction solution was concentrated under reduced pressure,additional toluene (3 ml) was added thereto, and the mixture was againconcentrated. To the resulting residue was added diethyl ether (0.5 ml)at room temperature, and the mixture was stirred. Next, n-hexane (2 ml)was added thereto, and the mixture was further stirred. The insolublesubstance was collected by filtration, and dried under reduced pressureto give the titled compound (52 mg).

¹H-NMR (DMSO-D₆) δ: 2.66 (s, 3H), 3.18 (dd, 1H, J=9.2, 5.7 Hz), 3.51(dd, 1H, J=9.2, 9.9 Hz), 4.12 (dd, 1H, J=9.9, 5.7 Hz), 6.42 (br s, 1H),12.99 (br s, 1H).

Also, Z-L-asparagine was subjected to the same reactions andpost-treatment as described above to give(S)-3-methyl-2-oxoimidazolidine-4-carboxylic acid (686 mg) as theoptical isomer of the titled compound.

¹H-NMR (DMSO-D₆) δ: 2.66 (s, 3H), 3.18 (dd, 1H, J=9.2, 5.7 Hz), 3.51(dd, 1H, J=9.2, 9.9 Hz), 4.12 (dd, 1H, J=9.9, 5.7 Hz), 6.42 (br s, 1H),12.99 (br s, 1H).

[Preparation 10]: Example 6: Synthesis of((R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide)

(1) (R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide

To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (56mg) prepared according to the same procedures as Preparation 8 inN,N-dimethylformamide (0.6 ml) were sequentially added(R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid (38 mg) prepared inPreparation 9, HOBt.H₂O (46 mg) and WSC.HCl (58 mg), and the mixture wasstirred at room temperature for 2 hours. To this reaction solution wereadded a saturated aqueous solution of sodium hydrogen carbonate andwater, and the mixture was extracted with ethyl acetate. The separatedorganic layer was washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelthin-layer chromatography (eluent: chloroform/methanol=10/1) to give thetitled compound (40 mg).

¹H-NMR (DMSO-D₆) δ: 0.77 (t, 3H, J=7.3 Hz), 1.44 (tq, 2H, J=7.5, 7.3Hz), 2.46 (t, 3H, J=7.5 Hz), 2.64 (s, 3H), 3.21 (dd, 1H, J=8.8, 6.3 Hz),3.54 (dd, 1H, J=9.4, 8.8 Hz), 4.28 (dd, 1H, J=9.4, 6.3 Hz), 6.44 (s,1H), 6.92 (s, 1H), 7.01 (s, 1H), 7.08 (d, 1H, J=7.0 Hz), 7.17 (d, 1H,J=7.0 Hz), 7.20-7.44 (m, 6H), 11.02 (s, 1H).

[Preparation 11]: Synthesis of 5-oxotetrahydrofuran-3-carboxylic acid

(1) Sodium 5-oxo-2,5-dihydrofuran-3-carboxylate

To a solution of itaconic acid (26.0 g) in water (35 ml) was addeddropwise bromine (10.3 ml) at room temperature while keeping atemperature of the reaction solution below 45° C., and then the mixturewas stirred at 30° C. for 15 minutes. To this reaction solution wasadded portionwise sodium hydrogen carbonate (33.6 g), and then themixture was heated to 55° C. To this reaction solution was addeddropwise a solution of sodium carbonate (10.6 g) in water (15 ml), andthen the mixture was stirred for 20 minutes. This reaction solution wasiced, and stirred for 1 hour. The precipitated solid was collected byfiltration, washed with cold water and ethanol, and then dried underreduced pressure to give the titled compound (16.8 g).

¹H-NMR (DMSO-d₆) δ: 4.83 (d, 2H, J=2.0 Hz), 5.93-5.95 (m, 1H).

(2) 5-Oxotetrahydrofuran-3-carboxylic acid

To a solution of sodium 5-oxo-2,5-dihydrofuran-3-carboxylate (150 mg) inwater (3 ml) was added 10 wt % palladium on carbon (30 mg), and themixture was stirred for 18 hours at room temperature under one atm. ofhydrogen. Under nitrogen atmosphere, an appropriate amount of amberliteIR-120 was added to the reaction solution, the mixture was stirred atroom temperature for 10 minutes, and then filtered through Celite. Thefiltrate was concentrated under reduced pressure, ethyl acetate wasadded to the resulting residue, the mixture was dried over sodiumsulfate, and then again concentrated under reduced pressure to give thetitled compound (83 mg).

¹H-NMR (DMSO-d₆) δ: 2.64 (dd, 1H, J=17.6, 6.2 Hz), 2.75 (dd, 1H, J=17.6,9.4 Hz), 3.39-3.49 (m, 1H), 4.34 (dd, 1H, J=8.8, 5.4 Hz), 4.44 (dd, 1H,J=8.8, 8.2 Hz), 12.82 (br s, 1H).

[Preparation 12]: Example 7: Synthesis of(5-oxotetrahydrofuran-3-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide)

(1) 5-Oxotetrahydrofuran-3-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide

To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (109mg) prepared according to the same procedures as Preparation 8 inN,N-dimethylformamide/tetrahydrofuran (1/1, 2 ml) were sequentiallyadded 5-oxotetrahydrofuran-3-carboxylic acid (82 mg) prepared inPreparation 9, HOBt.H₂O (96 mg) and WSC.HCl (121 mg), and the mixturewas stirred at room temperature overnight. To this reaction solution wasadded a saturated aqueous solution of sodium hydrogen carbonate, and themixture was extracted with ethyl acetate. The separated organic layerwas concentrated under reduced pressure, and the resulting residue waspurified by silica gel thin-layer chromatography (eluent:chloroform/methanol=10/1) to give the titled compound (96 mg).

¹H-NMR (DMSO-D₆) δ: 0.77 (t, 3H, J=7.3 Hz), 1.38-1.50 (m, 2H), 2.46 (t,2H, J=7.5 Hz), 2.69 (dd, 1H, J=17.4, 5.9 Hz), 2.81 (dd, 1H, J=17.4, 9.0Hz), 3.56-3.65 (m, 1H), 4.34 (dd, 1H, J=8.8, 5.0 Hz), 4.47-4.55 (m, 1H),6.89 (s, 1H), 7.00 (s, 1H), 7.07 (d, 1H, J=7.5 Hz), 7.17 (d, 1H, J=7.1Hz), 7.20-7.30 (3H, m), 7.31-7.43 (3H, m), 11.00 (s, 1H).

[Preparation 13]: Example 8: Synthesis of((R)-2-oxoimidazolidine-4-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide)

(1) (R)-2,3-Bis-tert-butoxycarbonylaminopropionic acid

To a solution of di-tert-butyl dicarbonate (513 mg) in 1,4-dioxane (4ml) was added N-Boc-(R)-2,3-diaminopropionic acid (400 mg) at roomtemperature, and the mixture was stirred for 20 minutes, and then heatedto 50° C., and stirred for 20 minutes. The mixture was again cooled toroom temperature, and then triethylamine (546 μl) was added thereto, andthe mixture was stirred for 2 hours. To this reaction solution wereadded water and a 10 wt % aqueous solution of citric acid, and themixture was extracted with ethyl acetate. The resulting organic layerwas washed twice with water, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluent: chloroform/ethanol=I/O to10/1) to give the titled compound (557 mg).

¹H-NMR (DMSO-D₆) δ: 1.37 (s, 9H), 1.38 (s, 9H), 3.23 (dd, 2H, J=6.2, 6.0Hz), 3.99 (dt, 1H, J=8.2, 6.2 Hz), 6.78 (t, 1H, J=6.0 Hz), 6.86 (d, 1H,J=8.2 Hz), 12.52 (br s, 1H).

(2){(R)-2-tert-Butoxycarbonylamino-2-[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylcarbamoyl]-ethyl}carbamicacid tert-butyl ester

To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (177mg) prepared according to the same procedures as Preparation 8 in DMF(1.8 ml) were added (R)-2,3-bis-tert-butoxycarbonylaminopropionic acid(292 mg), HOBt.H₂O (147 mg) and WSC.HCl (184 mg), and the mixture wasstirred at room temperature for 2 hours. To this reaction solution wereadded water and a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. Theseparated organic layer was washed with a saturated aqueous solution ofsodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1)to give the titled compound (329 mg).

¹H-NMR (CDCl₃) δ: 0.83 (t, 3H, J=7.3 Hz), 1.45 (s, 9H), 1.48 (s, 9H),1.50 (tq, 2H, J=7.3, 7.5 Hz), 2.49 (t, 2H, J=7.5 Hz), 3.61-3.64 (br m,2H), 4.38-4.41 (br m, 1H), 5.06 (br s, 1H), 5.94 (br s, 1H), 7.01 (s,1H), 7.05-7.35 (m, 9H), 8.94 (br s, 1H).

(3)(R)-2,3-Diamino-N-[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]-propionamidedihydrochloride

To a solution of[(R)-2-tert-butoxycarbonylamino-2-[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylcarbamoyl]-ethyl]carbamicacid tert-butyl ester (328 mg) in 1,4-dioxane (3 ml) was added a 4Msolution of hydrogen chloride in 1,4-dioxane (3 ml) at room temperature,and the mixture was stirred for 2 hours. This reaction solution wasconcentrated, and then n-hexane (4 ml) was added thereto, and themixture was stirred. The insoluble substance was collected byfiltration, washed with n-hexane, and dried under reduced pressure togive the titled compound (181 mg).

¹H-NMR (DMSO-D₆) δ: 0.77 (t, 3H, J=7.3 Hz), 1.44 (tq, 2H, J=7.5, 7.3Hz), 2.46 (t, 2H, J=7.5 Hz), 3.41-3.46 (m, 2H), 3.57 (s, 1H), 4.38-4.41(m, 1H), 6.91 (s, 1H), 7.11-7.31 (m, 9H), 8.56 (br s, 4H).

(4) (R)-2-Oxoimidazolidine-4-carboxylic acid[1-phenyl-5-(3-propyl-phenyl)-1H-pyrazol-3-yl]amide

To a solution of(R)-2,3-diamino-N-[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]-propionamidedihydrochloride (181 mg) in N,N-dimethylformamide (3 ml) were added1,1′-carbonyldiimidazole (67 mg), and triethylamine (116 μl) at roomtemperature, and the mixture was stirred for 16 hours. To this reactionsolution was added water, and the mixture was extracted with ethylacetate. The resulting organic layer was washed with water and asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel thin-layer chromatography(eluent: chloroform/methanol=10/1) to give the titled compound (76 mg).

¹H-NMR (DMSO-D₆) δ: 0.77 (t, 3H, J=7.4 Hz), 1.44 (tq, 2H, J=7.5, 7.4Hz), 2.46 (t, 2H, J=7.5 Hz), 3.35 (dd, 1H, J=9.4, 5.6 Hz), 3.59 (dd, 1H,J=9.4, 9.4 Hz), 4.32 (dd, 1H, J=9.4, 5.6 Hz), 6.34 (s, 1H), 6.61 (s,1H), 6.90 (s, 1H), 7.00 (s, 1H), 7.06-7.41 (m, 8H), 10.71 (s, 1H).

[Preparation 14]: Synthesis of (S)-5-oxopyrrolidine-3-carboxylic acid

(1)(S)-4-Benzyl-3-[(S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone

To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylicacid (20 g) prepared according to the same procedures as Preparation 5in chloroform (200 ml) were sequentially added(S)-4-benzyl-2-oxazolidinone (15.2 g) and WSC.HCl (16.4 g),4-(dimethylamino)pyridine (4.4 g) at room temperature, and the mixturewas stirred for 3 hours. This reaction solution was washed with a 5 wt %aqueous solution of sodium hydrogen carbonate and a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent: n-hexane/ethylacetate=1/1 to 1/3), subjected to azeotropic drying with toluene, anddried under reduced pressure to give the titled compound (17.2 g).

H-NMR (CDCl₃) δ: 2.72-2.83 (m, 3H), 3.27 (dd, 1H, J=13.4, 3.5 Hz),3.46-3.57 (m, 2H), 3.80 (s, 3H), 3.80 (s, 3H), 4.15-4.29 (m, 3H),4.40-4.48 (m, 2H), 4.61-4.69 (m, 1H), 6.42-6.47 (m, 2H), 7.12-7.21 (m,3H), 7.27-7.37 (m, 3H).

(2) (S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid

To a solution of lithium hydroxide monohydrate (2.0 g) in water (45 ml)was added dropwise 30 wt % aqueous solution of hydrogen peroxidesolution (11 ml)) in an ice-sodium chloride cooling bath, and themixture was stirred for 15 minutes. To this reaction solution was addedtetrahydrofuran (36 ml), and then a solution of(S)-4-benzyl-3-[(S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone(17.2 g) in tetrahydrofuran (144 ml) was added dropwise thereto, and themixture was stirred for additional 20 minutes. To this reaction solutionwas slowly added a 10 wt % aqueous solution of sodium hydrogen sulfite(131 ml), and the mixture was stirred at room temperature for 1 hourafter removing the bath, and then extracted with ethyl acetate (180 ml).The resulting organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluent: ethyl acetate tochloroform/methanol=9/1). To the resulting product (6.7 g) was addeddiisopropyl ether (13.4 ml), the mixture was stirred at 70° C., and thencooled to 0° C. with stirring. A solid was collected from thissuspension by filtration, dried under reduced pressure to give thetitled compound (5.5 g). An analysis of this solid by HPLC analysiscondition 1 showed that an isomer with longer retention time was a mainproduct.

An isomer with shorter retention time (retention time 4.7 minutes)

An isomer with longer retention time (retention time 5.4 minutes)

¹H-NMR (CDCl₃) δ: 2.66-2.82 (m, 2H), 3.20 (dt, 1H, J=17.3, 7.6 Hz),3.49-3.53 (m, 2H), 3.80 (s, 6H), 4.40 (d, 1H, J=14.6 Hz), 4.46 (d, 1H,J=14.6 Hz), 6.42-6.47 (m, 2H), 7.14 (t, 1H, J=4.5 Hz).

(3) (S)-5-oxopyrrolidine-3-carboxylic acid

To (S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (5.3g) were added anisole (3.1 ml) and trifluoroacetic acid (26.5 ml) atroom temperature, and the mixture was stirred for 4 hours at reflux.This reaction solution was cooled to room temperature, concentratedunder reduced pressure, azeotropic-dried with toluene. To the resultingresidue was added diisopropyl ether (53 ml), and the mixture was stirredat room temperature. A solid was collected from this suspension byfiltration, washed with diisopropyl ether, and dried under reducedpressure to give the titled compound (2.4 g).

¹H-NMR (DMSO-D₆) δ: 2.26-2.40 (m, 2H), 3.18-3.28 (m, 1H), 3.30-3.35 (m,1H), 3.40-3.47 (m, 1H), 7.64 (s, 1H), 12.58 (s, 1H)

[Preparation 15]: Example 235: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide)

(1) 1-Fluoro-3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)benzene

Under argon atmosphere, a suspension of sodium hydride (76 mg, 60 wt %oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0° C., asolution of N,N-dimethylformamide (2.0 ml) in(R)-1,1,1-trifluoropropan-2-ol (219 mg) was added thereto, and themixture was stirred for 25 minutes. Then, a solution of1-bromomethyl-3-fluorobenzene (297 mg) in N,N-dimethylformamide (2.0 ml)was added thereto, and then the mixture was stirred for 2 hours. To thisreaction mixture was added water, and the mixture was extracted withethyl acetate. This organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel thin-layer chromatography (eluent: n-hexane/ethylacetate=9/1) to give the titled compound (242 mg).

¹H-NMR (CDCl₃) δ: 1.35 (d, 3H, J=6.47 Hz), 3.84 (qq, 1H, J=6.47, 9.40Hz), 4.63 (d, 1H, J=12.00 Hz), 4.76 (d, 1H, J=12.00 Hz), 6.98-7.03 (m,1H), 7.06-7.12 (m, 2H), 7.29-7.35 (m, 1H).

(2)2-[3-Fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

Under argon atmosphere, to a solution of1-fluoro-3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)benzene (159 mg) intetrahydrofuran (3.0 ml) were sequentially added bispinacolate diboron(202 mg), 4,4′-di-tert-butyl-2,2′-dipyridyl (10 mg) anddi-μ-methoxobis(1,5-cyclooctadiene)diiridium (I) (12 mg) at roomtemperature, and then the mixture was stirred for 16 hours at reflux.This reaction mixture was cooled to room temperature, and then asaturated aqueous solution of sodium hydrogen carbonate and ethylacetate were added thereto, the mixture was filtered through Celite, andextracted with ethyl acetate. The filtrate was extracted with ethylacetate, the separated organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel thin-layer chromatography (eluent: n-hexane/ethylacetate=85/15) to give the titled compound (49 mg).

¹H-NMR (CDCl₃) δ: 1.35 (m, 15H), 3.83 (qq, 1H, J=6.47, 9.40 Hz), 4.62(d, 1H, J=12.00 Hz), 4.75 (d, 1H, J=12.00 Hz), 7.19 (d, 1H, J=9.60 Hz),7.43 (d, 1H, J=9.60 Hz), 7.49 (s, 1H).

(3)5-[3-Fluoro-5-((R)-2,2,2-trifluoro-1-methylethyethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine

To2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5-methyl-[1,3,2]dioxaborolane(49 mg) were sequentially added a solution of5-iodo-1-phenyl-1H-pyrazol-3-ylamine (36 mg) prepared according to thesame procedures as Preparation 2 in 1,2-dimethoxyethane (1.0 ml), a 2Maqueous solution of sodium carbonate (0.5 ml), tricyclohexylphosphine(7.3 mg) and palladium (II) acetate (3.0 mg) at room temperature, andthe mixture was stirred at 100° C. for 2 hours. This reaction mixturewas cooled to room temperature, a saturated aqueous solution of sodiumhydrogen carbonate and ethyl acetate were added thereto, the mixture wasfiltered through Celite, and extracted with ethyl acetate. The filtratewas extracted with ethyl acetate, the separated organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=9/1) to give the titledcompound (37 mg).

(4) (S)-5-Oxopyrrolidine-3-carboxylic acid{5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide

To a solution of5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine(37 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added(S)-5-oxopyrrolidine-3-carboxylic acid (16 mg) prepared in Preparation14 and WSC.HCl (23 mg) at room temperature, the mixture was stirred for5.2 hours. To this reaction mixture was added water, and then theprecipitated solid was collected by filtration. This solid was purifiedby silica gel thin-layer chromatography (eluent:chloroform/methanol=9/1). To the resulting solid were added water and asmall amount of methanol, and the mixture was stirred. A solid wascollected from this suspension by filtration, and was dried underreduced pressure to give the titled compound (20 mg).

¹H-NMR (DMSO-D6) δ:1.18 (d, 3H, J=6.5 Hz), 2.36-2.38 (m, 2H), 3.32-3.33(m, 1H), 3.37-3.41 (m, 1H), 3.46-3.49 (m, 1H), 4.10 (qq, 1H, J=6.5, 9.4Hz), 4.57 (d, 1H, J=12.7 Hz), 4.61 (d, 1H, J=12.7 Hz), 6.96-3.98 (m,2H), 7.09 (s, 1H), 7.15-7.18 (m, 1H), 7.25-7.27 (m, 2H), 7.35-7.44 (m,3H), 7.63 (s, 1H), 10.88 (s, 1H).

[Preparation 16]: Example 236: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{1-(4-chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide)

(1) 1-(4-Chlorophenyl)-3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole

Under argon atmosphere, to a solution of3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (3.06 g) prepared according tothe same procedures as Preparation 4 in N-methylpyrrolidone (31 ml) weresequentially added cesium carbonate (12.37 g), 8-quinolinol (0.55 g),copper (I) oxide (0.27 g) and 1-chloro-4-iodobenzene (6.79 g) at roomtemperature, the mixture was stirred at 110° C. for 2 hours. Thisreaction mixture was cooled to room temperature, and then toluene (30ml) was added thereto, the mixture was filtered through Celite, andfurther subjected to elution with toluene. The filtrate was sequentiallywashed with a 1N aqueous solution of sodium hydroxide, water, asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=1/0 to 9/1) to give the titled compound(4.98 g).

¹H-NMR (CDCl₃) δ: 2.19 (s, 6H), 5.90 (s, 2H), 6.40 (d, 1H, J=2.65 Hz),7.43 (d, 2H, J=8.82 Hz), 7.66 (d, 2H, J=8.82 Hz), 7.94 (d, 1H, J=2.65Hz).

(2) 1-(4-Chlorophenyl)-3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1H-pyrazole

Under argon atmosphere, a solution of3-(2,5-dimethylpyrrol-1-yl)-1-(4-chlorophenyl)-1H-pyrazole (4.98 g) intetrahydrofuran (40 ml) was cooled to −78° C., n-butyllithium (13.7 ml,1.6M solution in n-hexane) was added dropwise thereto, and the mixturewas stirred for 30 minutes. To this reaction solution was added dropwisea solution of iodine (5.58 g) in tetrahydrofuran (10 ml), the mixturewas stirred for 30 minutes. To this reaction solution were added a 20 wt% aqueous solution of sodium sulfite and a saturated aqueous solution ofammonium chloride, the mixture was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. To the resulting solid residue was added a mixedsolvent of ethyl acetate/n-hexane=1/2, the mixture was stirred. A solidwas collected from this suspension by filtration, and was dried underreduced pressure to give the titled compound (4.19 g).

¹H-NMR (CDCl₃) δ: 2.18 (s, 6H), 5.88 (s, 2H), 6.55 (s, 1H), 7.47 (d, 2H,J=9.04 Hz), 7.55 (d, 2H, J=9.04 Hz).

(3) 1-(4-Chlorophenyl)-5-iodo-1H-pyrazol-3-ylamine

To a suspension of1-(4-chlorophenyl)-3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1H-pyrazole (4.19g) in ethanol/water (2/1.72 ml) were sequentially added hydroxylammoniumchloride (14.64 g) and triethylamine (2.9 ml) at room temperature, andthe mixture was stirred at 95° C. for 86 hours. This reaction mixturewas cooled to room temperature, and concentrated under reduced pressure.To the resulting residue was added an 8M aqueous solution of sodiumhydroxide, and then the mixture was extracted with ethyl acetate. Thisorganic layer was sequentially washed with water and a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent: n-hexane/ethylacetate=2/1) to give the titled compound (1.87 g).

¹H-NMR (CDCl₃) δ: 3.77 (br s, 2H), 6.01 (s, 1H), 7.39-7.50 (m, 4H).

(4)1-(4-Chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine

Under argon atmosphere, to a solution of1-(4-chlorophenyl)-5-iodo-1H-pyrazol-3-ylamine (35 mg) in1,2-dimethoxyethane (0.7 ml) were sequentially added2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(46 mg) prepared according to the same procedures as Preparation 15, a2M aqueous solution of sodium carbonate (0.35 ml),tricyclohexylphosphine (6.1 mg) and palladium (II) acetate (2.5 mg) atroom temperature, and the mixture was stirred at 100° C. for 2 hours.This reaction mixture was cooled to room temperature, filtered throughCelite, was subjected to elution with ethyl acetate. The filtrate wasdried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The resulting residue was purified by silica gelthin-layer chromatography (eluent: n-hexane/ethyl acetate=1/1) to givethe titled compound.

(5) (S)-5-Oxopyrrolidine-3-carboxylic acid{1-(4-chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide

To a solution of1-(4-chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine(about 0.110 mol) prepared in the previous step in N,N-dimethylacetamide(0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid(17 mg) prepared in Preparation 14 and WSC.HCl (32 mg) at roomtemperature, and the mixture was stirred for 0.5 hours. To this reactionmixture was added water, and then the precipitated solid was collectedby filtration. The resulting solid was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=9/1) to give the titledcompound (18 mg).

¹H-NMR (DMSO-D6) δ:1.20 (d, 3H, J=6.5 Hz), 2.38-2.40 (m, 2H), 3.33-3.35(m, 1H), 3.40-3.44 (m, 1H), 3.48-3.51 (m, 1H), 4.10-4.15 (m, 1H), 4.63(s, 2H), 6.99 (s, 1H), 7.06 (s, 1H), 7.08 (d, 1H, J=9.3 Hz), 7.19 (d,1H, J=9.3 Hz), 7.27 (dd, 2H, J=6.6, 2.0 Hz), 7.48 (dd, 2H, J=6.6, 2.0Hz), 7.63 (s, 1H), 10.91 (s, 1H).

[Preparation 17]: Example 237: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{(1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide)

(1) 3-(2,5-Dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-1H-pyrazole

To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (1.00 g)prepared according to the same procedures as Preparation 4 inN-methylpyrrolidone (10 ml) were sequentially added1-fluoro-2-iodobenzene (1.08 ml), copper (I) oxide (89 mg), 8-quinolinol(180 mg) and cesium carbonate (4.04 g) at room temperature, and themixture was stirred at 110° C. for 3 hours. This reaction mixture wascooled to room temperature, and then toluene was added thereto, and themixture was filtered through Celite. The filtrate was sequentiallywashed with a 2N aqueous solution of sodium hydroxide, water and asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=1/0 to 10/1) to give the titled compound(1.19 g).

(2) 3-(2,5-Dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-5-iodo-1H-pyrazole

Under nitrogen atmosphere, a solution of3-(2,5-dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-1H-pyrazole (1.19 g) intetrahydrofuran (10 ml) was cooled to −78° C., n-butyllithium (3.5 ml,1.6M solution in n-hexane) was added dropwise thereto, and the mixturewas stirred for 30 minutes. To this reaction solution was added dropwisea solution of iodine (1.42 g) in tetrahydrofuran (5 ml), and the mixturewas stirred for 30 minutes. To this reaction mixture was added asaturated aqueous solution of sodium sulfite and a saturated aqueoussolution of ammonium chloride, and the mixture was extracted with ethylacetate. This organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. To the resulting residue was addeda mixed solvent of n-hexane/ethyl acetate (=6/1), the mixture wasstirred. A solid was collected from this suspension by filtration, andwas dried under reduced pressure to give the titled compound (1.23 g).

(3) 1-(2-Fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine

To a solution of3-(2,5-dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-5-iodo-1H-pyrazole (1.23g) in ethanol/water (2/1, 18 ml) were sequentially addedhydroxylammonium chloride (4.47 g) and triethylamine (0.9 ml) at roomtemperature, and the mixture was stirred at 90° C. for 24 hours. Thisreaction mixture was cooled to room temperature, concentrated underreduced pressure. To the resulting residue was added a 8M aqueoussolution of sodium hydroxide, and then the mixture was extracted withethyl acetate. This organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent: n-hexane/ethylacetate=4/1 to 1/1) to give the titled compound (0.61 g).

¹H-NMR (CDCl₃) δ: 3.76 (br s, 2H), 6.03 (s, 1H), 7.19-7.25 (m, 2H),7.38-7.46 (m, 2H).

(4)1-(2-Fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine

To a solution of 1-(2-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (38 mg)in 1,4-dioxane (0.4 ml) were sequentially added2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(52 mg) prepared according to the same procedures as Preparation 15,palladium (II) acetate (3 mg), tricyclohexylphosphine (7 mg), 2M aqueoussolution of potassium carbonate (0.2 ml) at room temperature, and themixture was stirred at 105° C. for 4 hours. After removing the aqueouslayer of this reaction mixture, the organic layer was filtered throughsilica gel (5 g), and subjected to elution with ethyl acetate. Thefiltrate was concentrated under reduced pressure, and the resultingresidue was purified by silica gel thin-layer chromatography (eluent:n-hexane/ethyl acetate 1/1) to give the titled compound.

(5) (S)-5-Oxopyrrolidine-3-carboxylic acid{1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide

To a solution of1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine(about 0.125 mmol) prepared in the previous step in dimethylformamide(0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid(18 mg) prepared in Preparation 14 and WSC.HCl (29 mg) at roomtemperature, and the mixture was stirred for 3 hours. To this reactionmixture was added water, and the mixture was extracted with ethylacetate. This organic layer was concentrated under reduced pressure, andthe resulting residue was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=10/1). To the resultingsolid were added water and a small amount of methanol, and the mixturewas stirred. A solid was collected from this suspension by filtration,and was dried under reduced pressure to give the titled compound (32mg).

¹H-NMR (CDCl₃) δ: 1.29 (d, 3H, J=6.4 Hz), 2.59 (dd, 1H, J=17.2, 9.6 Hz),2.78 (dd, 1H, J=17.2, 8.8 Hz), 3.29-3.40 (m, 1H), 3.60 (dd, 1H, J=9.2Hz), 3.67-3.80 (m, 2H), 4.52 (d, 1H, J=12.0 Hz), 4.63 (d, 1H, J=12.0Hz), 6.08 (s, 1H), 6.85 (dt, 1H, J=9.6, 2.0 Hz), 6.98-7.04 (m, 2H),7.09-7.17 (m, 2H), 7.22 (t, 1H, J=8.0 Hz), 7.34-7.22 (m, 2H), 8.69 (s,1H).

[Preparation 18]: Example 238: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide)

(1) 3-(2,5-Dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-1H-pyrazole

To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (500 mg)prepared according to the same procedures as Preparation4,4-fluorophenyl boronic acid (651 mg) and copper (II) acetate (563 mg)in chloroform (5 ml) was added pyridine (0.50 ml) at room temperature,the mixture was stirred for 40 hours. This reaction solution wasfiltered through silica gel, and subjected to elution with ethylacetate. The filtrate was concentrated under reduced pressure, theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=9/1) to give the titled compound (599mg).

¹H-NMR (CDCl₃) δ: 2.19 (s, 6H), 5.90 (s, 2H), 6.39 (d, 1H, J=2.56 Hz),7.15-7.17 (m, 2H), 7.67-7.70 (m, 2H), 7.91 (d, 1H, J=2.56 Hz).

(2) 3-(2,5-Dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-5-iodo-1H-pyrazole

Under argon atmosphere, a solution of3-(2,5-dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-1H-pyrazole (599 mg) intetrahydrofuran (4 ml) was cooled to −78° C., n-butyllithium (1.8 ml,1.6M solution in n-hexane) was added dropwise thereto, and the mixturewas stirred for 30 minutes. To this reaction solution was added dropwisea solution of iodine (715 mg) in tetrahydrofuran (2 ml), the mixture wasstirred for additional 30 minutes. To this reaction mixture was added asaturated aqueous solution of sodium sulfite, and the mixture wasextracted with ethyl acetate. The resulting organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.To the resulting solid residue was added a mixed solvent of ethylacetate/n-hexane (=1/5), and the mixture was stirred. A solid wascollected from this suspension by filtration, dried under reducedpressure to give the titled compound (625 mg).

¹H-NMR (CDCl₃) δ: 2.18 (s, 6H), 5.88 (s, 2H), 6.54 (s, 1H), 7.18-7.20(m, 2H), 7.54-7.57 (m, 2H).

(3) 1-(4-Fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine

To a suspension of3-(2,5-dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-5-iodo-1H-pyrazole (625mg) in ethanol/water (2/1, 12.5 ml) were sequentially addedhydroxylammonium chloride (2.28 g) and triethylamine (0.46 ml) at roomtemperature, and the mixture was stirred at 95° C. for 15 hours. Thisreaction mixture was cooled to room temperature, concentrated underreduced pressure. To the resulting residue was added a 8M aqueoussolution of sodium hydroxide, and then the mixture was extracted withethyl acetate. This organic layer was sequentially washed with water anda saturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (318mg).

¹H-NMR (CDCl₃) δ: 3.75 (br s, 2H), 6.00 (s, 1H), 7.11-7.15 (m, 2H),7.44-7.47 (m, 2H).

(4) (R)-3-[1,1,1-Trifluoropropan-2-yloxy]phenyl boronic acid

A solution of (R)-1,1,1-trifluoropropan-2-ol (212 mg) inN,N-dimethylformamide (1.5 ml) was cooled to 0° C., sodium hydride (74mg, 60 wt. % oil dispersion) and 3-(bromomethyl)phenyl boronic acid (100mg) were sequentially added thereto, and the mixture was stirred at roomtemperature for 2 hours. To this reaction mixture were added water andan 1M aqueous solution of hydrochloric acid, and the mixture wasextracted with ethyl acetate. This organic layer was washed with waterand a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated under reduced pressureto give the titled compound (147 mg).

(5)1-(4-Fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine

To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (70 mg)in 1,2-dimethoxyethane (0.7 ml) were sequentially added(R)-3-(1,1,1-trifluoropropan-2-yloxy)phenyl boronic acid (104 mg), a 2Maqueous solution of sodium carbonate (0.35 ml), tricyclohexylphosphine(13.0 mg) and palladium (II) acetate (5.2 mg) at room temperature, andthe mixture was stirred at 100° C. for 15 hours. This reaction mixturewas cooled to room temperature, filtered through Celite, and subjectedto elution with ethyl acetate. The filtrate was extracted with ethylacetate, the resulting organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent: n-hexane/ethylacetate=1/1) to give the titled compound (52 mg).

¹H-NMR (CDCl₃) δ: 1.28 (d, 3H, J=6.51 Hz), 3.74-3.80 (m, 2H), 3.76-3.78(m, 1H), 4.56 (d, 1H, J=11.86 Hz), 4.66 (d, 1H, J=11.86 Hz), 5.92 (s,1H), 6.96-6.99 (m, 2H), 7.15-7.21 (m, 4H), 7.29-7.29 (m, 2H).

(6) (S)-5-Oxopyrrolidine-3-carboxylic acid{1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide

To a solution of1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine(52 mg) in N,N-dimethylacetamide (0.5 ml) were sequentially added(S)-5-oxopyrrolidine-3-carboxylic acid (20 mg) prepared according to thesame procedures as Preparation 5 and WSC.HCl (40 mg) at roomtemperature, and the mixture was stirred for 0.5 hours. To this reactionmixture was added water, and then the precipitated solid was collectedby filtration. This solid was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=9/1). To the resulting solidwere added water and a small amount of methanol, and the mixture wasstirred. A solid was collected by filtration from this suspension, anddried under reduced pressure to give the titled compound (37 mg).

¹H-NMR (DMSO-D6) δ:1.20 (d, 3H, J=6.5 Hz), 2.38-2.39 (m, 2H), 3.33-3.34(m, 1H), 3.39-3.43 (m, 1H), 3.49-3.51 (m, 1H), 4.09-4.11 (m, 1H), 4.59(d, 1H, J=12.1 Hz), 4.63 (d, 1H, J=12.1 Hz), 6.92 (s, 1H), 7.18-7.39 (m,8H), 7.63 (s, 1H), 10.85 (s, 1H).

[Preparation 19]: Example 239: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide)

(1)1-(4-Fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine

To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (38 mg)prepared in Preparation 18 in 1,4-dioxane (0.4 ml) were sequentiallyadded2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(52 mg) prepared according to the same procedures as Preparation 15,palladium (II) acetate (3 mg), tricyclohexylphosphine (7 mg) and a 2Maqueous solution of potassium carbonate (0.2 ml) at room temperature,and the mixture was stirred at 105° C. for 4 hours. After removing anaqueous layer of the reaction mixture, an organic layer was filteredthrough silica gel (5 g), and subjected to elution with ethyl acetate.The filtrate was concentrated under reduced pressure, the resultingresidue was purified by silica gel thin-layer chromatography (eluent:n-hexane/ethyl acetate=1/1) to give the titled compound.

(2) (S)-5-Oxopyrrolidine-3-carboxylic acid{1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide

To a solution of1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamineprepared in the previous step (about 0.125 mmol) in dimethylformamide(0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid(18 mg) prepared according to the same procedures as Preparation 14 andWSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3hours. To this reaction mixture was added water, and the mixture wasextracted with ethyl acetate. This organic layer was concentrated underreduced pressure, the resulting residue was purified by silica gelthin-layer chromatography (eluent: chloroform/methanol=10/1). To theresulting solid were added water and a small amount of methanol, and themixture was stirred. A solid was collected from this suspension byfiltration, and was dried under reduced pressure to give the titledcompound (31 mg).

¹H-NMR (CDCl₃) δ:1.31 (d, 3H, J=6.4 Hz), 2.61 (dd, 1H, J=16.8, 9.6 Hz),2.78 (dd, 1H, J=16.8, 8.4 Hz), 3.31-3.42 (m, 1H), 3.61 (t, 1H, J=8.8Hz), 3.67-3.83 (m, 2H), 4.55 (d, 1H, J=12.0 Hz), 4.65 (d, 1H, J=12.0Hz), 6.04 (s, 1H), 6.85 (d, 1H, J=9.2 Hz), 6.98-7.10 (m, 5H), 7.19-7.25(m, 2H), 8.48 (s, 1H).

[Preparation 20]: Synthesis of (R)-2-oxoimidazolidine-4-carboxylic acid

(1) (R)-2-Oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester

Under ice-cooling, to a 1M aqueous solution of sodium hydroxide (124 ml)was added dropwise bromine (6.60 ml), and then after adding(R)-2-benzyloxycarbonylaminosuccinamic acid (10.0 g), the mixture wasstirred at 55° C. for 3 hours. This reaction solution was cooled to roomtemperature, washed twice with diethyl ether, and then a 6M aqueoussolution of hydrochloric acid (21 ml) was added thereto. This reactionmixture was left to stand at 4° C. for 3 days, and a precipitated solidwas collected by filtration to give the titled compound (6.16 g).

¹H-NMR (DMSO-D₆) δ: 3.19-3.22 (m, 1H), 3.63 (dd, 1H, J=10.2, 5.0 Hz),4.67 (dd, 1H, J=10.2, 3.3 Hz), 5.14-5.18 (m, 2H), 7.28-7.40 (m, 5H),7.56 (s, 1H), 13.24 (br s, 1H).

(2) (R)-2-Oxoimidazolidine-4-carboxylic acid

Under nitrogen atmosphere, to a solution of(R)-2-oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester (1.61 g) inmethanol/tetrahydrofuran (4/1, 20 ml) was added 10 wt % palladium oncarbon (161 mg) at room temperature, and the mixture was stirred for 24hours under one atmosphere of hydrogen. Under nitrogen atmosphere,palladium on carbon in this reaction solution was filtered off throughCelite, and the filtrate was concentrated under reduced pressure. To theresulting residue were added diisopropyl ether and n-hexane, and themixture was stirred. A solid was collected from this suspension byfiltration, and dried under reduced pressure to give the titled compound(565 mg).

¹H-NMR (DMSO-D₆) δ: 3.27 (ddd, 1H, J=9.8, 4.8, 0.8 Hz), 3.54 (dd, 1H,J=9.8, 9.8 Hz), 4.10 (dd, 1H, J=9.8, 4.8 Hz), 6.24 (s, 1H), 6.56 (s,1H), 12.83 (br s, 1H).

[Preparation 21]: Example 240: Synthesis of((R)-2-oxoimidazolidine-4-carboxylic acid{1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide)

(1)1-(4-Fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine

To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (84 mg)prepared according to the same procedures as Preparation 18 in1,4-dioxane (1.0 ml) were sequentially added2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(106 mg) prepared according to the same procedures as Preparation 15,palladium (II) acetate (7 mg), tricyclohexylphosphine (17 mg) and a 2Maqueous solution of potassium carbonate (0.5 ml) at room temperature,and the mixture was stirred at 105° C. for 2 hours. This reactionmixture was cooled to room temperature and after removing an aqueouslayer, an organic layer was filtered through silica gel (5 g), andsubjected to elution with ethyl acetate. The filtrate was concentratedunder reduced pressure, and the resulting residue was purified by silicagel thin-layer chromatography (eluent: n-hexane/ethyl acetate=3/2) togive the titled compound.

(2) (R)-2-Oxoimidazolidine-4-carboxylic acid{1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide

To a solution of1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine(about 0.277 mmol) prepared in the previous step in chloroform (1 ml)were sequentially added (R)-2-oxoimidazolidine-4-carboxylic acid (40 mg)and WSC.HCl (64 mg) at room temperature, and the mixture was stirred for3 hours. This reaction mixture was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=10/1). To the resultingsolid were added water and a small amount of methanol, and the mixturewas stirred. A solid was collected from this suspension by filtrationand was dried under reduced pressure to give the titled compound (56mg).

¹H-NMR (DMSO-D₆) δ: 1.20 (d, 3H, J=6.0 Hz), 3.35 (dd, 1H, J=8.6, 6.2Hz), 3.58 (dd, 1H, J=9.3, 8.6 Hz), 4.12 (tq, 1H, J=9.7, 6.0 Hz), 4.31(dd, 1H, J=9.3, 6.2 Hz), 4.60 (d, 1H, J=12.5 Hz), 4.63 (d, 1H, J=12.5Hz), 6.33 (s, 1H), 6.59 (s, 1H), 6.98 (s, 1H), 7.02-7.07 (m, 2H), 7.18(d, 1H, J=9.6 Hz), 7.23-7.35 (m, 4H), 10.72 (s, 1H).

[Preparation 22]: Example 241: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide)

(1) 1-Chloro-3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)benzene

Under argon atmosphere, a suspension of sodium hydride (77 mg, 60 wt %oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0° C., asolution of (R)-1,1,1-trifluoropropan-2-ol (213 mg) inN,N-dimethylformamide (2.0 ml) was added thereto, and the mixture wasstirred for 15 minutes. Then, a solution of1-bromomethyl-3-chlorobenzene (311 mg) in N,N-dimethylformamide (2.0 ml)was added thereto, and then the mixture was stirred at room temperaturefor 2.5 hours. To this reaction mixture was added water, and the mixturewas extracted with ethyl acetate. This organic layer was washed with asaturated aqueous solution of sodium chloride, dried over magnesiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel chromatography (eluent:n-hexane/ethyl acetate=1/0 to 19/1) to give the titled compound (307mg).

¹H-NMR (CDCl₃) δ: 1.35 (d, 3H, J=6.47 Hz), 3.84 (qq, 1H, J=6.47, 9.40Hz), 4.62 (d, 1H, J=12.00 Hz), 4.73 (d, 1H, J=12.00 Hz), 7.21-7.24 (m,1H), 7.27-7.30 (m, 2H), 7.34 (s 1H)

(2)2-[3-Chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl[1,3,2]dioxaborolane

Under argon atmosphere, to a solution of1-chloro-3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)benzene (307 mg) intetrahydrofuran (6.0 ml) were sequentially added bispinacolate diboron(362 mg), 4,4′-di-tert-butyl-2,2′-dipyridyl (18 mg) anddi-g-methoxobis(1,5-cyclooctadiene)diiridium (1) (22 mg) at roomtemperature, and then the mixture was heated to reflux for 13 hours.After cooling this reaction mixture to room temperature, a saturatedaqueous solution of sodium hydrogen carbonate and ethyl acetate wereadded thereto, the mixture was filtered through Celite. The filtrate wasextracted with ethyl acetate. The resulting organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by silica gel thin-layerchromatography (eluent: n-hexane/ethyl acetate=9/1) to give the titledcompound (374 mg).

¹H-NMR (CDCl₃) δ: 1.35 (m, 15H), 3.83 (qq, 1H, J=6.47, 9.40 Hz), 4.59(d, 1H, J=12.00 Hz), 4.73 (d, 1H, J=12.00 Hz), 7.46 (s, 1H), 7.59 (d,1H, J=9.60 Hz), 7.72 (s, 1H).

(3)5-[3-Chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine

Under argon atmosphere, to2-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl[1,3,2]dioxaborolane(269 mg) were sequentially added a solution of5-iodo-1-phenyl-1H-pyrazol-3-ylamine (181 mg) prepared according to thesame procedures as Preparation 2 in 1,2-dimethoxyethane (2.0 ml), a 2Maqueous solution of sodium carbonate (1.0 ml), tricyclohexylphosphine(36 mg) and palladium (II) acetate (15 mg) at room temperature, and themixture was stirred at 100° C. for 2 hours. This reaction mixture wascooled to room temperature, a saturated aqueous solution of sodiumhydrogen carbonate and ethyl acetate were added thereto, the mixture wasfiltered through Celite, and subjected to elution with ethyl acetate.The filtrate was extracted with ethyl acetate. The resulting organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate, and then concentrated underreduced pressure. The resulting residue was purified by silica gelthin-layer chromatography (eluent: n-hexane/ethyl acetate=3/7) to givethe titled compound (196 mg).

(4) (S)-5-Oxopyrrolidine-3-carboxylic acid{5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide

To a solution of5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine(79 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added(S)-5-oxopyrrolidine-3-carboxylic acid (31 mg) prepared according to thesame procedures as Preparation 14 and WSC.HCl (47 mg) at roomtemperature, and the mixture was stirred overnight. To this reactionmixture was added water, and then the precipitated solid was collectedby filtration. This solid was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=9/1). To the resulting solidwere added water and a small amount of methanol, and the mixture wasstirred. A solid was collected from this suspension by filtration andwas dried under reduced pressure to give the titled compound (60 mg).

¹H-NMR (DMSO-D6) δ:1.18 (d, 3H, J=6.5 Hz), 2.36-2.38 (m, 2H), 3.32-3.33(m, 1H), 3.37-3.41 (m, 1H), 3.46-3.49 (m, 1H), 4.10 (qq, 1H, J=6.5, 9.4Hz), 4.57 (d, 1H, J=12.7 Hz), 4.61 (d, 1H, J=12.7 Hz), 6.98 (s, 1H),7.19-7.20 (m, 2H), 7.25-7.27 (m, 2H), 7.35-7.45 (m, 4H), 7.63 (s, 1H),10.88 (s, 1H).

[Preparation 23]: Example 242: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-yl}amide)

(1)5-[3-Chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-ylamine

To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (50 mg)prepared according to the same procedures as Preparation 18 in1,2-dimethoxyethane (0.5 ml) were sequentially added2-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(72 mg) prepared according to the same procedures as Preparation 22, a2M aqueous solution of sodium carbonate (0.25 ml),tricyclohexylphosphine (9.3 mg) and palladium (II) acetate (3.7 mg) atroom temperature, and the mixture was stirred at 100° C. for 2 hours.This reaction mixture was cooled to room temperature, filtered throughCelite, and subjected to elution with ethyl acetate. The filtrate wasextracted with ethyl acetate, the resulting organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=1/1) to give the titledcompound (79 mg).

¹H-NMR (CDCl₃) δ: 1.29 (d, 3H, J=6.47 Hz), 3.75 (qq, 1H, J=6.47, 9.40Hz), 3.78 (br s, 2H), 4.50 (d, 1H, J=12.02 Hz), 4.61 (d, 1H, J=12.02Hz), 5.93 (s, 1H), 6.99-7.02 (m, 3H), 7.18-7.20 (m, 3H), 7.26-7.28 (m,1H).

(2) (S)-5-Oxopyrrolidine-3-carboxylic acid{5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-yl}amide

To a solution of5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-ylamine(79 mg) in chloroform (0.4 ml) were sequentially added(S)-5-oxopyrrolidine-3-carboxylic acid (26 mg) prepared according to thesame procedures as Preparation 14 and WSC.HCl (47 mg) at roomtemperature, and the mixture was stirred for 2 hours. This reactionmixture was purified by silica gel thin-layer chromatography (eluent:chloroform/methanol=9/1). To the resulting solid were added water and asmall amount of methanol, and the mixture was stirred. A solid wascollected from this suspension by filtration and was dried under reducedpressure to give the titled compound (43 mg).

¹H-NMR (DMSO-D6) δ 1.18 (d, 3H, J=6.5 Hz), 2.36-2.38 (m, 2H), 3.32-3.33(m, 1H), 3.37-3.41 (m, 1H), 3.46-3.49 (m, 1H), 4.10 (qq, 1H, J=6.5, 9.4Hz), 4.57 (d, 1H, J=12.7 Hz), 4.61 (d, 1H, J=12.7 Hz), 6.97 (s, 1H),7.13 (s, 1H), 7.23-7.32 (m, 5H), 7.37 (s, 1H), 7.61 (s, 1H), 10.86 (s,1H).

[Preparation 24]: Example 243 Synthesis of(S)-5-oxopyrrolidine-3-carboxylic acid[5-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl]amide)

(1) 1-Chloro-3-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)benzene

To a suspension cooled to 0° C. of sodium hydride (126 mg, 60 wt. % oildispersion) in N,N-dimethylformamide (5 ml) was added dropwise,1,1,1-trifluoro-2-methylpropan-2-ol (320 μL) under argon atmosphere, andthe mixture was stirred for 15 minutes. To this reaction mixture wasadded dropwise 1-bromomethyl-3-chlorobenzene (320 μL), and the mixturewas stirred for 3 hours. To this reaction mixture was added water, andthe mixture was extracted with ethyl acetate. This organic layer waswashed with water and a saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=1/0 to 40/1) to give thetitled compound (389 mg).

¹H-NMR (CDCl₃) δ: 1.45 (s, 6H), 4.50 (s, 2H), 7.15-7.30 (m, 3H), 7.34(s, 1H).

(2)2-[3-Chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

Under argon atmosphere, to a solution of1-chloro-3-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)benzene (389 mg) intetrahydrofuran (4 ml) were sequentially added bispinacolate diboron(430 mg), 4,4′-di-tert-butyl-2,2′-dipyridyl (21 mg),di-μ-methoxobis(1,5-cyclooctadiene)diiridium (I) (29 mg) at roomtemperature, and the mixture was heated to reflux for 13 hours. Thisreaction mixture was cooled to room temperature, a saturated aqueoussolution of sodium hydrogen carbonate was added thereto, and the mixturewas extracted with ethyl acetate. This organic layer was dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=100/1 to 20/1) to give the titledcompound (481 mg).

¹H-NMR (CDCl₃) δ: 1.34 (s, 12H), 1.44 (s, 6H), 4.57 (s, 2H), 7.45 (s,1H), 7.57 (s, 1H), 7.69 (s, 1H).

(3)5-[3-Chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine

Under argon atmosphere, to a solution of5-iodo-1-phenyl-1H-pyrazol-3-ylamine (40 mg) prepared according to thesame procedures as Preparation 2 in 1,2-dimethoxyethane (1.0 ml) weresequentially added2-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(64 mg), palladium (II) acetate (3 mg), tricyclohexylphosphine (8 mg)and a 2M aqueous solution of sodium carbonate (0.5 ml) at roomtemperature, and the mixture was stirred at 100° C. for 13 hours. Thisreaction mixture was cooled to room temperature, and then purified bysilica gel column chromatography (eluent: n-hexane/ethyl acetate 3/2 to1/1) to give the titled compound (62 mg).

¹H-NMR (CDCl₃) δ:1.35 (s, 6H), 3.77 (br s, 2H), 4.46 (s, 2H), 5.93 (s,1H), 7.00 (s, 1H), 7.15 (s, 1H), 7.20-7.26 (m, 4H), 7.28-7.33 (m, 2H).

(4) (S)-5-Oxopyrrolidine-3-carboxylic acid{5-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide)

Under argon atmosphere, to a solution of5-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine(62 mg) in N,N-dimethylacetamide (1 ml) were sequentially added(S)-5-oxopyrrolidine-3-carboxylic acid (26 mg) prepared according to thesame procedures as Preparation 14, WSC.HCl (40 mg) at room temperature,and the mixture was stirred for 1 hour. To this reaction mixture wasadded water, and the mixture was extracted with ethyl acetate. Thisorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. The resulting residue was purified by silica gelthin-layer chromatography (eluent: chloroform/methanol=9/1). To theresulting solid were added water and a small amount of methanol, and themixture was stirred. A solid was collected from this suspension byfiltration, and was dried under reduced pressure to give the titledcompound (35 mg).

¹H-NMR (DMSO-D₆) δ:1.32 (s, 6H), 2.37-2.42 (m, 2H), 3.33-3.53 (m, 3H),4.53 (s, 2H), 6.98 (s, 1H), 7.16 (s, 1H), 7.19 (s, 1H), 7.23-7.28 (m,2H), 7.33-7.45 (m, 4H), 7.63 (s, 1H), 10.89 (s, 1H).

[Preparation 25]: Example 244: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{1-(4-chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide)

(1) 2-(3-Bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

To a solution of 3-(bromomethyl)phenyl boronic acid (3.13 g) in ethylacetate (45 ml) were sequentially added pinacol (1.72 g) and anhydrousmagnesium sulfate (15 g) at room temperature, and the mixture wasstirred for 8 hours. The insoluble substance was filtered off, and thefiltrate was concentrated under reduced pressure to give the titledcompound (4.43 g).

¹H-NMR (CDCl₃) δ:1.33 (s, 12H), 4.49 (s, 2H), 7.31-7.37 (m, 1H),7.46-7.50 (m, 1H), 7.70-7.74 (m, 1H), 7.79-7.82 (m, 1H).

(2)4,4,5,5-Tetramethyl-2-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl)-[1,3,2]dioxaborolane

Under argon stream, to a solution of (R)-1,1,1-trifluoropropan-2-ol(3.32 g) in N,N-dimethylformamide (43 ml) was added portionwise sodiumhydride (1.16 g, 60 wt % oil dispersion) at 0° C., and the mixture wasstirred for 20 minutes. Then,2-(3-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.32g) was added thereto, and then the mixture was stirred at roomtemperature overnight. To this reaction mixture were sequentially addedwater and a 2M aqueous solution of hydrochloric acid, and the mixturewas extracted with ethyl acetate. This organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=1/0 to 19/1) to give the titled compound(3.43 g).

¹H-NMR (CDCl₃) δ: 1.31 (d, 3H, J=6.6 Hz), 1.35 (s, 12H), 3.77-3.89 (m,1H), 4.62 (d, 1H, J=11.7 Hz), 4.76 (d, 1H, J=11.7 Hz), 7.35-7.43 (m,1H), 7.46-7.54 (m, 1H), 7.71-7.81 (m, 2H).

(3)1-(4-Chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine

To a solution of 11-(4-chlorophenyl)-5-iodo-1H-pyrazol-3-ylamine (40 mg)prepared in Preparation 16 in 1,4-dioxane (0.4 ml) were sequentiallyadded4,4,5,5-tetramethyl-2-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl)-[1,3,2]dioxaborolane(50 mg), palladium (II) acetate (3 mg), tricyclohexylphosphine (7 mg)and a 2M aqueous solution of potassium carbonate (0.2 ml) at roomtemperature, and the mixture was stirred at 105° C. for 4 hours. Afterremoving an aqueous layer of the reaction mixture, an organic layer wasfiltered through silica gel (5 g), and subjected to elution with ethylacetate. The filtrate was concentrated under reduced pressure, theresulting residue was purified by silica gel thin-layer chromatography(eluent: n-hexane/ethyl acetate=1/1) to give the titled compound.

(4) (S)-5-Oxopyrrolidine-3-carboxylic acid{1-(4-chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide

To a solution of1-(4-chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine(about 0.125 mmol) prepared in the previous step inN,N-dimethylformamide (1 ml) were sequentially added(S)-5-oxopyrrolidine-3-carboxylic acid prepared according to the sameprocedures as preparation 14 (18 mg) and WSC.HCl (29 mg) at roomtemperature, and the mixture was stirred for 3 hours. To this reactionmixture was added water, and the mixture was extracted with ethylacetate. The resulting organic layer was concentrated under reducedpressure, the resulting residue was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=10/1). To the resultingsolid were added water and a small amount of methanol, and the mixturewas stirred. A solid was collected from this suspension by filtration,and was dried under reduced pressure to give the titled compound (33mg).

¹H-NMR (CDCl₃) δ: 1.29 (d, 3H, J=6.8 Hz), 2.61 (dd, 1H, J=17.2, 9.6 Hz),2.78 (dd, 1H, J=17.2, 8.8 Hz), 3.30-3.40 (m, 1H), 3.61 (t, 1H, J=8.8Hz), 3.68-3.82 (m, 2H), 4.57 (d, 1H, J=12.0 Hz), 4.68 (d, 1H, J=12.0Hz), 5.90 (s, 1H), 7.04 (s, 1H), 7.15-7.20 (m, 3H), 7.24 (br s, 1H),7.28-7.35 (m, 4H), 8.38 (s, 1H).

[Preparation 26]: Example 245: Synthesis of((R)-2-oxoimidazolidine-4-carboxylic acid[5-(3-butylphenyl)-1-phenyl-1H-pyrazol-3-yl]amide)

(1) 1-Bromo-3-butylbenzene

Under nitrogen stream, to a solution of 1-bromo-3-bromomethylbenzene (25g) in tetrahydrofuran (200 ml) were sequentially added dropwisen-propylmagnesium bromide (60 ml, 2M solution in tetrahydrofuran) andlithium tetrachlorocuprate (5 ml, 0.1M solution in tetrahydrofuran) at−78° C. Then, this reaction mixture was stirred at 0° C. for 2 hours.Under ice-cooling, to this reaction mixture were sequentially added asaturated aqueous solution of ammonium chloride (100 ml) and water (100ml), and the mixture was extracted with ethyl acetate (200 ml). Theresulting aqueous layer was again extracted with ethyl acetate (100 ml),the combined organic layer was washed with a saturated aqueous solutionof sodium chloride (100 ml), and dried over anhydrous sodium sulfate.This organic layer was concentrated under reduced pressure, theresulting residue was purified by silica gel chromatography (eluent:n-hexane/ethyl acetate=1/0 to 100/1) to give the titled compound (8.5g).

¹H-NMR (CDCl₃) δ: 0.91 (t, 3H, J=7.4 Hz), 1.31-1.35 (m, 2H), 1.55-1.59(m, 2H), 2.56 (t, 2H, J=7.8 Hz), 7.06-7.13 (m, 2H), 7.27-7.32 (m, 2H).

(2) 2-(3-Butylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

Under argon atmosphere, to a solution of 1-bromo-3-butylbenzene (1.44 g)in 1,4-dioxane (15 ml) were added bispinacolate diboron (1.97 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)dichloromethane adduct (287 mg) and potassium acetate (2.07 g) at roomtemperature, and the mixture was stirred at 80° C. for 15 hours. Themixture was cooled to room temperature, and the insoluble substance wasfiltered off through Celite. The filtrate was washed with water and asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=30/1 to 10/1) to give the titledcompound (1.37 g).

¹H-NMR (CDCl₃) δ: 0.92 (t, 3H, J=7.3 Hz), 1.31-1.41 (m, 14H), 1.59-1.61(m, 2H), 2.61 (t, 2H, J=7.9 Hz), 7.24-7.30 (m, 2H), 7.59-7.65 (m, 2H).

(3) 5-(3-Butylphenyl)-1-phenyl-1H-pyrazol-3-ylamine

To a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (1.00 g) preparedaccording to the same procedures as Preparation 2 in 1,2-dimethoxyethane(20 ml) were sequentially added2-(3-butylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.37 g), a2M aqueous solution of sodium carbonate (10 ml), tricyclohexylphosphine(197 mg) and palladium acetate (79 mg) at room temperature, and themixture was stirred at reflux for 3 hours. This reaction mixture wascooled to room temperature, a saturated aqueous solution of sodiumhydrogen carbonate was added thereto, and then the insoluble substancewas filtered off through Celite. The filtrate was extracted with ethylacetate, the resulting organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1to 2/3) to give the titled compound (880 mg).

¹H-NMR (CDCl₃) δ: 0.85 (t, 3H, J=7.3 Hz), 1.17-1.27 (m, 2H), 1.40-1.47(m, 2H), 2.49 (t, 2H, J=7.6 Hz), 3.75 (br s, 2H), 5.90 (s, 1H), 6.97 (s,1H), 7.02-7.12 (m, 2H), 7.13-7.29 (m, 6H).

(4) (R)-2-Oxoimiadazolidine-4-carboxylic acid[5-(3-butylphenyl)-1-phenyl-1H-pyrazol-3-yl]amide

To a solution of 5-(3-butylphenyl)-1-phenyl-1H-pyrazol-3-ylamine (40 mg)in N,N-dimethylformamide (0.4 ml) were sequentially added(R)-2-oxoimidazolidine-4-carboxylic acid (21 mg) prepared by the sameprocedures as Preparation 20, HATU (63 mg), diisopropylethylamine (29μL) at room temperature, and the mixture was stirred for 2 hours. Tothis reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The resulting organic layer was washed with waterand a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting residue was purified by silica gel thin-layerchromatography (eluent: n-hexane/acetone=1/5). To the resulting solidwas added diisopropyl ether, and the mixture was stirred. A solid wascollected from this suspension by filtration, and was dried underreduced pressure to give the titled compound (12 mg).

¹H-NMR (DMSO-D6) δ: 0.82 (t, 3H, J=7.4 Hz), 1.15 (tq, 2H, J=7.4 Hz, 7.4Hz), 1.39 (tt, 2H, J=7.4 Hz, 7.4 Hz), 2.48 (t, 2H, J=7.4 Hz), 3.36 (dd,1H, J=9.2 Hz, 5.6 Hz), 3.59 (dd, 1H, J=9.2 Hz, 9.2 Hz), 4.32 (dd, 1H,J=9.2 Hz, 5.6 Hz), 6.33 (s, 1H), 6.60 (s, 1H), 6.90 (s, 1H), 6.98 (s,1H), 7.09 (d, 1H, J=7.6 Hz), 7.17 (d, 1H, J=7.6 Hz), 7.20-7.30 (m, 3H),7.32-7.43 (m, 3H), 10.70 (s, 1H).

[Preparation 27]: Example 246: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{1-phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide)

(1) 3-(1,1,1,3,3,3-Hexafluoropropan-2-yloxy)phenyl boronic acid

A suspension of sodium hydride (149 mg, 60 wt. % oil dispersion) inN,N-dimethylformamide (3.0 m) was cooled to 0° C.,(R)-1,1,1,3,3,3-hexafluoropropan-2-ol (392 mg) was added thereto, andthe mixture was stirred for 15 minutes. Then, 3-(bromomethyl)phenylboronic acid (200 mg) was added thereto, and then the mixture wasstirred at room temperature for 2 hours. To this reaction mixture weresequentially added water and a 1M aqueous solution of hydrochloric acid,and the mixture was extracted with ethyl acetate. This organic layer waswashed with a saturated aqueous solution of sodium chloride, dried overmagnesium sulfate, and then concentrated under reduced pressure to givea crude product of the titled compound (1.0 g).

(2)1-Phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine

To 3-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)phenyl boronic acid (1.0 g)were sequentially added a solution of5-iodo-1-phenyl-1H-pyrazol-3-ylamine (180 mg) prepared according to thesame procedures as Preparation 2 in 1,2-dimethoxyethane (2.0 ml), a 2Maqueous solution of sodium carbonate (1.0 ml), tricyclohexylphosphine(35 mg) and palladium (II) acetate (18 mg) at room temperature, and themixture was stirred at 100° C. for 2 hours. This reaction mixture wascooled to room temperature, filtered through Celite, and subjected toelution with ethyl acetate. The filtrate was extracted with ethylacetate, the resulting organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over magnesium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel thin-layer chromatography (eluent: n-hexane/ethylacetate=3/7) to give the titled compound (151 mg).

(3) (S)-5-Oxopyrrolidine-3-carboxylic acid{1-phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide

To a solution of1-phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl)phenyl]-1H-pyrazol-3-ylamine(78 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added(S)-5-oxopyrrolidine-3-carboxylic acid (29 mg) prepared according to thesame procedures as Preparation 5 and WSC.HCl (44 mg) at roomtemperature, and the mixture was stirred overnight. To this reactionmixture was added water, and then the precipitated solid was collectedby filtration. The resulting solid was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=9/1). To the resulting solidwere added water and a small amount of methanol, and the mixture wasstirred. A solid was collected from this suspension by filtration, andwas dried under reduced pressure to give the titled compound (54 mg).

¹H-NMR (DMSO-D6) δ: 2.36-2.38 (m, 2H), 3.32-3.33 (m, 1H), 3.37-3.41 (m,1H), 3.46-3.49 (m, 1H), 4.85 (m, 2H), 5.53-5.59 (m, 1H), 6.94 (s, 1H),7.17-7.18 (m, 1H), 7.22-7.24 (m, 2H), 7.34-7.41 (m, 6H), 7.63 (s, 1H),10.88 (s, 1H).

[Preparation 28]: Example 247: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{1-(4-fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide)

(1) 1-Bromo-3-(2,2,2-trifluoroethoxymethyl)benzene

Under nitrogen atmosphere, a suspension of sodium hydride (352 mg, 60wt. % oil dispersion) in tetrahydrofuran (10 ml) was cooled to 0° C.,2,2,2-trifluoroethanol (0.63 ml) was added thereto, and the mixture wasstirred for 5 minutes. Then, 3-bromobenzyl bromide (2.00 g) was addedthereto, and then the mixture was stirred at reflux for 1 hour. Thisreaction mixture was cooled to room temperature, a saturated aqueoussolution of ammonium chloride was added thereto, and the mixture wasextracted with ethyl acetate. This organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=1/0 to 10/1) to give the titled compound(2.05 g).

¹H-NMR (CDCl₃) δ: 3.84 (q, 2H, J=8.68 Hz), 4.65 (s, 2H), 7.22-7.28 (m,2H), 7.45-7.47 (m, 1H), 7.49-7.51 (m, 1H).

(2)4,4,5,5-Tetramethyl-2-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,3,2]dioxaborolane

Under argon atmosphere, to a solution of1-bromo-3-(2,2,2-trifluoroethoxymethyl)benzene (2.05 g) in 1,4-dioxane(21 ml) were sequentially added bispinacolate diboron (2.12 g),potassium acetate (2.24 g) and[1,1′-bis(diphenylphosfino)ferrocene]dichloropalladium (II)dichloromethane adduct (310 mg) at room temperature, and the mixture wasstirred at 80° C. for 19 hours. This reaction mixture was cooled to roomtemperature, filtered through Celite, and then subjected to elution withethyl acetate. The filtrate was concentrated under reduced pressure, theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=30/1) to give the titled compound (1.69g).

¹H-NMR (CDCl₃) δ:1.35 (s, 12H), 3.81 (q, 2H, J=8.67 Hz), 4.68 (s, 2H),7.38-7.40 (m, 1H), 7.47-7.48 (m, 1H), 7.76-7.78 (m, 2H).

(3)1-(4-Fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine

Under argon atmosphere, to a solution of1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (70 mg) prepared inPreparation 18 in 1,2-dimethoxyethane (0.7 ml) were sequentially added4,4,5,5-tetramethyl-2-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,3,2]dioxaborolane(80 mg), a 2M aqueous solution of sodium carbonate (0.35 ml),tricyclohexylphosphine (13.0 mg) and palladium (II) acetate (5.2 mg) atroom temperature, and the mixture was stirred at 100° C. for 2 hours.This reaction mixture was cooled to room temperature, filtered throughCelite, and subjected to elution with ethyl acetate. The filtrate wasextracted with ethyl acetate, the resulting organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (43mg).

¹H-NMR (CDCl₃) δ: 3.74 (q, 2H, J=8.61 Hz), 3.77 (br s, 2H), 4.60 (s,2H), 5.93 (s, 1H), 6.97-6.99 (m, 2H), 7.16-7.21 (m, 4H), 7.29-7.31 (m,2H).

(4) (S)-5-Oxopyrrolidine-3-carboxylic acid{1-(4-fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide

To a solution of1-(4-fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine(43 mg) in N,N-dimethylacetamide (0.4 ml) were sequentially added(S)-5-oxopyrrolidine-3-carboxylic acid (17 mg) prepared according to thesame procedures as Preparation 5 and WSC.HCl (34 mg) at roomtemperature, and the mixture was stirred for 0.5 hours. To this reactionmixture was added water, and then the precipitated solid was collectedby filtration. This solid was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=9/1). To the resulting solidwere added water and a small amount of methanol, and the mixture wasstirred. A solid was collected from this suspension by filtration, andwas dried under reduced pressure to give the titled compound (26 mg).

¹H-NMR (DMSO-D6) δ: 2.38-2.40 (m, 2H), 3.32-3.35 (m, 1H), 3.40-3.45 (m,1H), 3.48-3.52 (m, 1H), 3.98 (q, 2H, J=9.3 Hz), 4.61 (s, 2H), 6.93 (s,1H), 7.18-7.40 (m, 8H), 7.63 (s, 1H), 10.86 (s, 1H).

[Preparation 29]: Example 248: Synthesis of((S)-5-oxopyrrolidine-3-carboxylic acid{1-(4-fluorophenyl)-5-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide)

(1) 1-Chloro-3-fluoro-5-(2,2,2-trifluoroethoxymethyl)benzene

Under argon stream, to a suspension of sodium hydride (601 mg, 60 wt. %oil dispersion) in dimethylformamide (13 ml) was added dropwisetrifluoroethanol (1.08 ml) at 0° C., and the mixture was stirred for 15minutes. To this reaction solution was added dropwise a solution of1-chloro-3-fluoro-5-chloromethylbenzene (2.23 g) in dimethylformamide (9ml), and then the mixture was stirred at room temperature for 1 hour. Tothis reaction mixture was added water, and the mixture was extractedwith a mixed solvent of n-hexane/ethyl acetate=1/1. This organic layerwas washed with a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=1/0 to 9/1) to give thetitled compound (2.85 g).

¹H-NMR (CDCl₃) δ: 3.87 (q, 2H, J=8.8 Hz), 4.64 (s, 2H), 6.97 (d, 1H,J=8.8 Hz), 7.05 (dt, 1H, J=8.8, 2.4 Hz), 7.13 (br s, 1H).

(2)2-[3-Fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

Under argon atmosphere, to a solution of1-chloro-3-fluoro-5-(2,2,2-trifluoroethoxymethyl)benzene (2.65 g) in1,4-dioxane (60 ml) were sequentially added bispinacolate diboron (3.41g), potassium acetate (3.33 g),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (521 mg) andtris(dibenzylideneacetone) dipalladium (0) (253 mg) at room temperature,and the mixture was stirred at reflux for 6 hours. This reaction mixturewas cooled to room temperature, and then filtered through Celite, andsubjected to elution with ethyl acetate. The filtrate was concentratedunder reduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: n-hexane/ethyl acetate=1/0 to 19/1). Theresulting crude product was suspended in n-hexane, and the insolublesubstance was filtered off. The filtrate was concentrated under reducedpressure to give the titled compound (2.71 g).

¹H-NMR (CDCl₃) δ: 1.35 (s, 12H), 3.83 (q, 2H, J=8.8 Hz), 4.67 (s, 2H),7.18 (d, 1H, J=8.8 Hz), 7.44 (dd, 1H, J=8.8, 2.4 Hz), 7.50 (br s, 1H).

(3)1-(4-Chlorophenyl)-5-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine

To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (38 mg)prepared in Preparation 18 in 1,4-dioxane (0.4 ml) were sequentiallyadded2-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(50 mg), palladium (II) acetate (3 mg), tricyclohexylphosphine (7 mg)and a 2M aqueous solution of potassium carbonate (0.2 ml) at roomtemperature, and the mixture was stirred at 105° C. for 4 hours. Afterremoving an aqueous layer of the reaction mixture, an organic layer wasfiltered through silica gel (5 g), and subjected to elution with ethylacetate. The filtrate was concentrated under reduced pressure, theresulting residue was purified by silica gel thin-layer chromatography(eluent: n-hexane/ethyl acetate 1/1) to give the titled compound.

(4) Synthesis of (S)-5-oxopyrrolidine-3-carboxylic acid{1-(4-fluorophenyl)-5-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide

To a solution of1-(4-chlorophenyl)-5-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine(about 0.125 mmol) prepared in the previous step inN,N-dimethylformamide (0.5 ml) were sequentially added(S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) prepared according to thesame procedures as preparation 14 and WSC.HCl (29 mg) at roomtemperature, and the mixture was stirred for 3 hours. To this reactionmixture was added water, and the mixture was extracted with ethylacetate. This organic layer was concentrated under reduced pressure, theresulting residue was purified by silica gel thin-layer chromatography(eluent: chloroform/methanol=10/1). To the resulting solid were addedwater and a small amount of methanol, and the mixture was stirred. Asolid was collected from this suspension by filtration and was driedunder reduced pressure to give the titled compound (33 mg).

¹H-NMR (CDCl₃) δ: 2.61 (dd, 1H, J=17.2, 9.6 Hz), 2.78 (dd, 1H, J=17.2,8.8 Hz), 3.32-3.42 (m, 1H), 3.61 (t, 1H, J=8.8 Hz), 3.71 (dd, 1H, J=9.6,7.2 Hz), 3.79 (q, 2H, J=8.8 Hz), 4.59 (s, 2H), 6.04 (s, 1H), 6.89 (d,1H, J=9.2 Hz), 6.99-7.10 (m, 5H), 7.19-7.24 (m, 2H), 8.48 (s, 1H).

[Preparation 30]: Example 249: Synthesis of(4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide)

(1) 2-(tert-Butyldimethylsilanyloxymethyl)-2-propen-1-ol

Under argon atmosphere, to a suspension of sodium hydride (490 mg, 60wt. % oil dispersion) in tetrahydrofuran (10 ml) were sequentially added2-methylene-1,3-propanediol (1 ml) and tert-butyldimethylchlorosilane(2.22 g) at 0° C., and then the mixture was stirred at room temperaturefor 1 hour. To this reaction mixture was added a saturated aqueoussolution of ammonium chloride, and the mixture was extracted with ethylacetate. This organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1)to give the titled compound (1.62 g).

¹H-NMR (CDCl₃) δ: 0.09 (s, 6H), 0.91 (s, 9H), 1.96 (t, 1H, J=3.09 Hz),4.18 (d, 2H, J=3.09 Hz), 4.25 (s, 2H), 5.08 (d, 1H, J=1.32 Hz), 5.10 (d,1H, J=1.32 Hz).

(2) [2-(tert-Butyldimethylsilanyloxymethyl)allyl]-(2,4-dimethoxybenzyl)amine

To a solution of 2-(tert-butyldimethylsilanyloxymethyl)-2-propen-1-ol(1.58 g) in chloroform (16 ml) were sequentially added triethylamine(2.2 ml) and methanesulfonyl chloride (0.73 ml) at 0° C., and then themixture was stirred for 2 hours. To this reaction solution weresequentially added triethylamine (1.2 ml) and 2,4-dimethoxybenzylamine(1.3 ml), and then the mixture was stirred at room temperature for 15hours. To this reaction mixture was added water, and an organic layerwas separated from the mixture, and concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography(eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (1.14g).

¹H-NMR (CDCl₃) δ: 0.07 (s, 6H), 0.91 (s, 9H), 3.21 (s, 2H), 3.69 (s,2H), 3.80 (s, 6H), 4.18 (s, 2H), 5.02 (s, 1H), 5.13 (s, 1H), 6.41-6.45(m, 2H), 7.12 (d, 1H, J=7.91 Hz).

(3) (E)-2-(2-Tosylhydrazono)acetic acid

To glyoxylic acid monohydrate (644 mg) was added water (7 ml). Theresulting suspension was dissolved in water by heating to 65° C., asolution of p-toluenehydrazide (1.30 g) in a 2.5M aqueous solution ofhydrochloric acid (4.2 ml) was added thereto, and the mixture wasstirred for 15 minutes. This reaction mixture was cooled to roomtemperature, the precipitated solid was collected by filtration, andwashed with water. The resulting solid was dried under reduced pressureto give the titled compound (1.42 g).

¹H-NMR (CDCl₃) δ: 2.46 (s, 3H), 7.14 (s, 1H), 7.38 (d, 2H, J=8.14 Hz),7.83 (d, 2H, J=8.14 Hz), 8.46 (s, 1H).

(4) Diazoacetic acid 2,5-dioxopyrrolidin-1-yl ester

Under argon atmosphere, to a solution of (E)-2-(2-tosylhydrazono)aceticacid (1.42 g) in 1,4-dioxane (14 ml) were sequentially addedN-hydroxysuccinimide (677 mg) and dicyclohexylcarbodiimide (1.21 g) atroom temperature, and the mixture was stirred for 17 hours. Thisreaction mixture was filtered through Celite, and eluted with1,4-dioxane. This filtrate was concentrated under reduced pressure, theresulting residue was purified by silica gel column chromatography(eluent: n-hexane/diethyl ether=1/3) to give the titled compound (579mg).

¹H-NMR (CDCl₃) δ: 2.85 (s, 4H), 5.11 (s, 1H).

(5)N-[2-(tert-Butyldimethylsilanyloxymethyl)allyl]-2-diazo-N-(2,4-dimethoxybenzyl)acetamide

To a solution of[2-(tert-butyldimethylsilanyloxymethyl)allyl]-(2,4-dimethoxybenzyl)amine(384 mg) in chloroform (3.8 ml) were sequentially added triethylamine(0.23 ml) and diazoacetic acid 2,5-dioxopyrrolidin-1-yl ester (200 mg)at room temperature, and the mixture was stirred for 16 hours. Thisreaction mixture was concentrated under reduced pressure, the resultingresidue was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate=4/1) to give the titled compound (223 mg).

¹H-NMR (CDCl₃) δ: 0.06 (s, 6H), 0.90 (s, 9H), 3.79 (s, 3H), 3.80 (s,3H), 3.88-3.91 (m, 2H), 4.08 (s, 2H), 4.93 (s, 1H), 5.04 (s, 1H), 5.18(s, 1H), 6.43-6.47 (m, 3H).

(6)5-(tert-Butyldimethylsilanyloxymethyl)-3-(2,4-dimethoxybenzyl)-3-azabicyclo[3.1.0]hexan-2-one

Under argon atmosphere, to a solution ofN-[2-(tert-butyldimethylsilanyloxymethyl)allyl]-2-diazo-N-(2,4-dimethoxybenzyl)acetamide(43 mg) in benzotrifluoride (0.4 ml) was added rhodium (II) acetatedimer dihydrate (2.4 mg) at room temperature, and the mixture wasstirred at 50° C. for 24 hours. This reaction mixture was concentratedunder reduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: n-hexane/ethyl acetate=2/1) to give thetitled compound (14.2 mg).

¹H-NMR (CDCl₃) δ: 0.01 (s, 6H), 0.72 (dd, 1H, J=4.42, 3.61 Hz), 0.85 (s,9H), 1.11 (dd, 1H, J=8.84, 4.42 Hz), 1.81 (dd, 1H, J=8.84, 3.61 Hz),3.16 (d, 1H, J=10.47 Hz), 3.36 (d, 1H, J=10.47 Hz), 3.62 (d, 1H, J=10.70Hz), 3.70 (d, 1H, J=10.70 Hz), 3.79 (s, 3H), 3.79 (s, 3H), 4.25 (d, 1H,J=14.65 Hz), 4.38 (d, 1H, J=14.65 Hz), 6.40-6.44 (m, 2H), 7.06-7.09 (m,1H).

(7)3-(2,4-Dimethoxybenzyl)-5-hydroxymethyl-3-azabicyclo[3.1.0]hexan-2-one

To a solution of5-(tert-butyldimethylsilanyloxymethyl)-3-(2,4-dimethoxybenzyl)-3-azabocyclo[3.1.0]hexan-2-one(14.2 mg) in tetrahydrofuran (0.3 ml) was added n-butylammonium fluoride(5491, 1.0M solution in tetrahydrofuran) at room temperature, and themixture was stirred for 1 hour. This reaction mixture was concentratedunder reduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate, tochloroform/methanol=9/1) to give the titled compound (9.2 mg).

¹H-NMR (CDCl₃) δ: 0.77 (dd, 1H, J=4.84, 3.43 Hz), 1.12 (dd, 1H, J=8.87,4.84 Hz), 1.85 (dd, 1H, J=8.87, 3.43 Hz), 3.23 (d, 1H, J=10.07 Hz), 3.45(d, 1H, J=10.07 Hz), 3.66 (d, 1H, J=11.69 Hz), 3.70 (d, 1H, J=11.69 Hz),3.79 (s, 3H), 3.79 (s, 3H), 4.21 (d, 1H, J=14.51 Hz), 4.43 (d, 1H,J=14.51 Hz), 6.41-6.44 (m, 2H), 7.07-7.10 (m, 1H).

(8)3-(2,4-Dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carbaldehyde

Under argon atmosphere, to a solution of3-(2,4-dimethoxybenzyl)-5-hydroxymethyl-3-azabicyclo[3.1.0]hexan-2-one(9.2 mg) in dimethylsulfoxide/chloroform (2/1,135 μl) were sequentiallyadded triethylamine (23 μl) and sulfur trioxide-pyridine complex (10.6mg) at room temperature, and the mixture was stirred for 2 hours. Tothis reaction mixture was added water, and the mixture was extractedwith ethyl acetate. This organic layer was washed with water, asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure to give acrude product of the titled compound (10.8 mg).

(9) 3-(2,4-Dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylicacid

Under argon atmosphere, to a solution of3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carbaldehyde(10.8 mg) in tert-butanol/tetrahydrofuran/water (4/3/1,0.5 ml) was addedsodium dihydrogenphosphate dihydrate (20.2 mg) at room temperature. Thisreaction mixture was cooled to 0° C., 2-methyl-2-butene (18 μl) andsodium chlorite (9.0 mg) were sequentially added thereto, and then themixture was stirred at room temperature for 24 hours. This reactionmixture was cooled to 0° C., and then water was added thereto, and themixture was extracted with ethyl acetate. This organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The resulting residue was purified by silica gel thin-layerchromatography (eluent: chloroform/methanol=9/1) to give the titledcompound (3.7 mg).

¹H-NMR (CDCl₃) δ: 0.69-0.71 (m, 1H), 1.68-1.71 (m, 1H), 2.25-2.28 (m,1H), 3.11 (d, 1H, J=11.28 Hz), 3.49 (s, 1H), 3.71 (s, 3H), 3.73 (s, 3H),3.75 (d, 1H, J=11.28 Hz), 3.98 (d, 1H, J=13.30 Hz), 4.42 (d, 1H, J=13.30Hz), 6.33-6.38 (m, 2H), 6.95-6.98 (m, 1H).

(10)3-(2,4-Dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylicacid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide

To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (3.5mg) prepared according to the same procedures as Preparation 2-2 inN,N-dimethylformamide (0.5 ml) were sequentially added3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylicacid (3.7 mg) and WSC.HCl (3.6 mg) at room temperature, and the mixturewas stirred for 14 hours. To this reaction mixture were addeddiisopropylethylamine (3.3 μl) and HATU (7.3 mg), and the mixture wasstirred at room temperature for additional 72 hours. To this reactionmixture was added water, and the mixture was extracted with ethylacetate. This organic layer was washed with water and a saturatedaqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure to give the titledcompound (6.3 mg).

(11) 4-Oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide

To 3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylicacid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide (6.3 mg) weresequentially added anisole (2 μl) and trifluoroacetic acid (0.5 ml) atroom temperature, and the mixture was stirred at 80° C. for 3 hours.This reaction mixture was concentrated under reduced pressure, theresulting residue was purified by silica gel thin-layer chromatography(eluent: chloroform/methanol=9/1) to give the titled compound (0.3 mg).

1H-NMR (CDCl3) δ: 0.83-0.88 (m, 4H), 1.22-1.28 (m, 3H), 1.95 (dd, 1H,J=9.3, 4.8 Hz), 2.49 (t, 2H, J=8.5 Hz), 3.60 (d, 1H, J=10.1 Hz), 4.01(d, 1H, J=10.1 Hz), 5.14 (s, 1H), 6.99 (s, 1H), 7.04-7.34 (m, 9H), 7.83(s, 1H).

[Preparation 31]: Example 250: Synthesis of(4-oxo-5-azabispiro[2.4]heptane-7-carboxylic acid{1-phenyl-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide)

(1) 1-Acetylcyclopropanecarboxylic acid methyl ester

To a solution of methyl acetoacetate (3 ml) in acetone (30 ml) weresequentially added potassium carbonate (11.54 g) and 1,2-dibromoethane(2.4 ml) at room temperature, and the mixture was stirred at 65° C. for17 hours. This reaction mixture was filtered, the filtrate wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (eluent: n-hexane/ethylacetate=10/1) to give the titled compound (2.17 g).

¹H-NMR (CDCl₃) δ: 1.48 (s, 4H), 2.47 (s, 3H), 3.75 (s, 3H).

(2) 1-(1-Trifluoromethanesulfonyloxyvinyl)cyclopropane carboxylic acidmethyl ester

Under argon atmosphere, to a solution of diisopropylamine (2.37 ml) intetrahydrofuran (11 ml) was added n-butyllithium (10.4 ml, 1.6M solutionin n-hexane) at 0° C., and the mixture was stirred for 0.5 hours. At−78° C., a solution of 1-acetylcyclopropane carboxylic acid methyl ester(2.17 g) in tetrahydrofuran (11 ml) was added thereto, and the mixturewas stirred for 0.5 hours. Then,N-phenylbis(trifluoromethanesulfonimide) (6.00 g) was added thereto, andthe mixture was stirred for 0.5 hours, and then stirred at 0° C. foradditional 1 hour. To this reaction mixture was added water, and themixture was extracted with ethyl acetate. This organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated under reduced pressureto give the titled compound (4.36 g).

(3) 1-(1-Methoxycarbonylvinyl)cyclopropanecarboxylic acid methyl ester

To a solution of 1-(1-trifluoromethanesulfonyloxyvinyl)cyclopropanecarboxylic acid methyl ester (4.36 g) prepared in the previous step inN,N-dimethylformamide/methanol (1/2, 66 ml) were sequentially addedtriethylamine (6.4 ml) and bis (triphenylphosphine)palladium (II)dichloride (1.07 g) at room temperature, and the air in reaction vesselwas replaced with carbon monooxide at normal pressure. This reactionsolution was stirred at 50° C. for 18 hours, and then cooled to roomtemperature, and carbon monooxide in the reaction vessel was replacedwith nitrogen. To this reaction mixture were added water and ethylacetate, the mixture was filtered through Celite, and subjected toelution with ethyl acetate. The filtrate was extracted with ethylacetate, the separated organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent: n-hexane/ethylacetate=8/1) to give the titled compound (720 mg).

¹H-NMR (CDCl₃) δ: 1.03 (dd, 2H, J=7.33, 4.07 Hz), 1.51 (dd, 2H, J=7.33,4.07 Hz), 3.65 (s, 3H), 3.78 (s, 3H), 5.64 (d, 1H, J=0.93 Hz), 6.31 (d,1H, J=0.93 Hz).

(4) 5-(2,4-Dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylicacid methyl ester

To a solution of 1-(1-methoxycarbonylvinyl)cyclopropanecarboxylic acidmethyl ester (720 mg) in toluene (3.6 ml) was added2,4-dimethoxybenzylamine (587 μl) at room temperature, and then themixture was stirred at reflux for 20 hours. This reaction mixture wasconcentrated under reduced pressure, the resulting residue was purifiedby silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1)to give the titled compound (567 mg).

¹H-NMR (CDCl₃) δ: 0.81-0.84 (m, 2H), 1.09-1.12 (m, 1H), 1.22-1.28 (m,1H), 3.10 (dd, 1H, J=8.84, 5.23 Hz), 3.48 (dd, 1H, J=10.00, 8.84 Hz),3.66 (dd, 1H, J=10.00, 5.23 Hz), 3.67 (s, 3H), 3.80 (s, 3H), 3.81 (s,3H), 4.45 (d, 1H, J=14.77 Hz), 4.51 (d, 1H, J=14.77 Hz), 6.45-6.47 (m,2H), 7.16-7.18 (m, 1H).

(5) 5-(2,4-Dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylicacid

To a solution of5-(2,4-dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acidmethyl ester (2.02 g) in tetrahydrofuran/methanol (1/1, 12 ml) was addeda 1M aqueous solution of sodium hydroxide (12 ml) at room temperature,and the mixture was stirred for 1 hour. To this reaction solution wasadded a 2M aqueous solution of hydrochloric acid (6 ml), and the mixturewas stirred, and then concentrated under reduced pressure. The resultingresidue was dissolved in ethyl acetate, the solution was washed with asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. To theresulting solid was added diisopropyl ether (8 ml), and the mixture wasstirred. A solid was collected from this suspension by filtration, andwas dried under reduced pressure to give the titled compound (1.59 g).

¹H-NMR (CDCl₃) δ: 0.83-0.88 (m, 1H), 0.95-1.00 (m, 1H), 1.12-1.18 (m,1H), 1.21-1.28 (m, 1H), 3.10 (dd, 1H, J=8.61, 5.12 Hz), 3.49 (dd, 1H,J=10.23, 8.61 Hz), 3.64 (dd, 1H, J=10.23, 5.12 Hz), 3.78 (s, 3H), 3.79(s, 3H), 4.43 (d, 1H, J=14.65 Hz), 4.50 (d, 1H, J=14.65 Hz), 6.42-6.45(m, 2H), 7.13-7.16 (m, 1H).

(6) Optically Active Compound of7-((R)-4-Benzyl-2-oxooxazolidine-3-carbonyl)-5-(2,4-dimethoxybenzyl)-5-azaspiro[2.4]heptan-4-one

To a solution of5-(2,4-dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acid(1.59 g) in chloroform (16 ml) were sequentially added(R)-4-benzyl-2-oxazolidinone (1.11 g), WSC.HCl (1.20 g) andN,N-dimethyl-4-aminopyridine (318 mg) at room temperature, and themixture was stirred for 4 hours. To this reaction mixture was addedwater, and the organic layer was separated from the solution, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1)to separate a low-polarity component as the titled compound (1.39 g).

¹H-NMR (CDCl₃) δ: 0.77-0.82 (m, 1H), 1.11-1.17 (m, 2H), 1.26-1.30 (m,1H), 2.67 (dd, 1H, J=13.23, 10.37 Hz), 3.38 (dd, 1H, J=13.23, 3.42 Hz),3.49-3.55 (m, 1H), 3.65 (dd, 1H, J=10.37, 3.42 Hz), 3.81 (s, 3H), 3.81(s, 3H), 4.17-4.19 (m, 2H), 4.34-4.36 (m, 1H), 4.48 (d, 1H, J=15.00 Hz),4.57 (d, 1H, J=15.00 Hz), 4.64-4.68 (m, 1H), 6.45-6.50 (m, 2H),7.21-7.24 (m, 3H), 7.29-7.37 (m, 3H).

(7) Optically Active Compound of5-(2,4-Dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acid

To a solution of lithium hydroxide monohydrate (142 mg) in water (5 ml)was added 30 wt % aqueous solution of hydrogen peroxide (0.8 ml) at −5°C., and the mixture was stirred for 15 minutes. To this reaction mixturewere sequentially added tetrahydrofuran (5 ml) and a solution of anoptically active compound of7-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-(2,4-dimethoxybenzyl)-5-azaspiro[2.4]heptan-4-one(1.39 g) in tetrahydrofuran (10 ml), and the mixture was stirred foradditional 1 hour. To this reaction mixture was added a solution ofsodium hydrogen sulfite (815 mg) in water (5 ml), and the mixture wasstirred at room temperature for 1 hour, and then extracted with ethylacetate. This organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluent: ethyl acetate only). To theresulting solid was added diisopropyl ether/ethyl acetate/n-hexane(10/1/5, 10 ml), and the mixture was stirred. A solid was collected fromthis suspension by filtration, and dried under reduced pressure to givethe titled compound (372 mg).

¹H-NMR (DMSO-D₆) δ: 0.83-0.89 (m, 3H), 0.94-0.97 (m, 1H), 3.07-3.11 (m,1H), 3.42-3.51 (m, 2H), 3.75 (s, 3H), 3.78 (s, 3H), 4.28 (d, 1H, J=14.89Hz), 4.34 (d, 1H, J=14.89 Hz), 6.49 (dd, 1H, J=8.37, 2.33 Hz), 6.57 (d,1H, J=2.33 Hz), 7.04 (d, 1H, J=8.37 Hz), 12.56 (br s, 1H).

(8) Optically Active Compound of4-Oxo-5-azaspiro[2.4]heptane-7-carboxylic acid

To an optically active compound of5-(2,4-dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acid(372 mg) were sequentially added anisole (159 μl) and trifluoroaceticacid (5.6 ml) at room temperature, and the mixture was stirred at 80° C.for 4 hours. This reaction mixture was concentrated under reducedpressure, and diisopropyl ether (10 ml) was added thereto. Theprecipitated solid was collected by filtration to give the titledcompound (144 mg).

¹H-NMR (DMSO-D₆) δ: 0.77-0.82 (m, 3H), 0.86-0.91 (m, 1H), 3.12 (t, 1H,J=6.75 Hz), 3.48 (d, 2H, J=6.75 Hz), 7.70 (br s, 1H), 12.51 (br s, 1H).

(9)1-Phenyl-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine

To a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (221 mg) preparedaccording to the same procedures as Preparation 2 in 1,2-dimethoxyethane(2.2 ml) were sequentially added4,4,5,5-tetramethyl-2-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,3,2]dioxaborolane(269 mg) prepared in Preparation 28, a 2M aqueous solution of sodiumcarbonate (1.1 ml), tricyclohexylphosphine (43.4 mg) and palladium (II)acetate (17.4 mg) at room temperature, and the mixture was stirred at100° C. for 12 hours. To this reaction mixture was added a saturatedaqueous solution of sodium hydrogen carbonate at room temperature, andthen the mixture was filtered through Celite, and subjected to elutionwith ethyl acetate. The filtrate was extracted with ethyl acetate, theresulting organic layer was washed with was a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1)to give the titled compound (258 mg).

¹H-NMR (CDCl₃) δ: 3.66 (q, 2H, J=8.7 Hz), 3.77 (br s, 2H), 4.57 (s, 2H),5.92 (s, 1H), 7.12-7.33 (m, 9H).

(10) Optically Active Compound of4-Oxo-5-azabispiro[2.4]heptane-7-carboxylic acid{1-phenyl-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide

To a solution of1-phenyl-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine(19.5 mg) in N,N-dimethylacetamide (0.2 ml) were sequentially added anoptically active compound of 4-oxo-5-azaspiro[2.4]heptane-7-carboxylicacid (10.5 mg) and WSC.HCl (16.1 mg) at room temperature, and themixture was stirred for 0.5 hours. To this reaction mixture was addedwater, and then the precipitated solid was collected by filtration, anddried under reduced pressure to give the titled compound (15.4 mg).

¹H-NMR (DMSO-D₆) δ: 0.66-0.71 (m, 1H), 0.78-0.82 (m, 1H), 0.88-0.99 (m,2H), 3.33-3.37 (m, 1H), 3.50-3.54 (m, 1H), 3.56-3.60 (m, 1H), 3.97 (q,2H, J=9.30 Hz), 4.61 (s, 2H), 6.93 (s, 1H), 7.15-7.17 (m, 1H), 7.22-7.26(m, 3H), 7.31-7.41 (m, 5H), 7.72 (s, 1H), 10.73 (s, 1H).

Compounds of Examples 9 to 234 and 251 to 605 were prepared according tothe same procedures as Preparations described in above. The compounds ofExamples 9 to 234 are shown in the following Tables 1 together withCompounds of Examples 1-8. The compounds of Examples 251 to 605 areshown in the following Tables 2 together with Compounds of Examples235-250.

Lengthy table referenced here US20180346449A1-20181206-T00001 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20180346449A1-20181206-T00002 Pleaserefer to the end of the specification for access instructions.

In the table 2, Structure Information A, B, C, D and E (Examples 255,256, 275, 277, 307, 309, 397, 398, 404 and 405) are the information onthe enantiomer derived from an asymmetric carbon atom of thealphaposition of carbonyl group. Said enantiomer was isolated andpurified according to the similar method as the Auxiliary step 2 of thePreparation Method 3-1 above.

Structure Information A (Examples 255 and 256)

Example 255 was synthesized using a high-polarity component obtained bysilicagel thin-layer chromatography (eluent: ethyl acetate) between thefollowing Compound [60] or Compound [61]. Example 256 was synthesizedusing a low-polarity component.

Structure Information B (Examples 275 and 277)

Example 275 was synthesized using a low-polarity component obtained bysilicagel thin-layer chromatography (eluent: n-hexane/ethyl acetate=1/3)between the following Compound [62] or Compound [63]. Example 277 wassynthesized using a high polarity component.

Structure Information C (Examples 307 and 309)

Example 307 was synthesized using a low-polarity component obtained bysilicagel thin-layer chromatography (eluent: n-hexane/ethyl acetate=1/1)between the following Compound [64] or Compound [65]. Example 309 wassynthesized using a high-polarity component.

Structure Information D (Examples 397 and 398)

Example 397 was synthesized using a low-polarity component obtained bysilicagel thin-layer chromatography (eluent: n-hexane/ethyl acetate=3/7)between the following Compound [66] or Compound [67]. Example 398 wassynthesized using a high-polarity component.

Structure Information E (Examples 404 and 405)

Example 404 was synthesized using a low-polarity component obtained bysilicagel thin-layer chromatography (eluent: chloroform/ethylacetate=1/1) between the following Compound [68] or Compound [69].Example 405 was synthesized using a high-polarity component.

Test Example

SGLT1 inhibitory activity of a test compound (IC₅₀ value) was calculatedbased on an amount of intake into a cell of labeledα-methyl-D-glucopyranoside (¹⁴C-AMG) which is transported by SGLT1.

1) Construction of Human SGLT1 Expression Plasmid

A DNA fragment containing human SGLT1, wherein NheI recognition andcleavage sequence was added upstream of a Kozac consensus sequence ofthe vector; and a stop codon (TAG) and a SalI recognition and cleavagesequence was added just downstream of a coding region of the humanSGLT1, was amplified by PCR using pCMV6-hSGLT1 (OriGene) as a template.The purified DNA fragment was cleaved by restriction enzymes NheI andSalI, and the obtained fragment was ligated into pcDNA3.1 (+) which wascleaved by NheI and XhoI to construct human SGLT1 expression plasmid.The nucleic acid sequence of human SGLT1 inserted into the vector wascompletely identical to the coding region of human SGLT1 sequence(Accession number NM_000343) registered in GenBank. In addition, thesequence which connects the inserted nucleic acid sequence to the vectorwas those to be expected.

2) Establishment of Stable Cell Lines Expressing Human SGLT1

A human SGLT1 expression plasmid pcDNA-hSGLT1 was transfected intoCHO-K1 cells by Lipofectamine2000 (Invitrogen). The cells were culturedin the presence of G418 (Nakalai tesque) and drug-resistant cells wereselected. A cell line having the highest S/B ratio of an amount of¹⁴C-AMG uptake per cell treated by solvent to an amount of ¹⁴C-AMGuptake per cell treated by phlorizin (SGLT inhibitor) was selected fromthe drug-resistant cells as a stable cell lines expressing human SGLT1.

3) Evaluation of SGLT1 Inhibitory Activity

The stable cell line expressing human SGLT1 was seeded at 5×10⁴cells/well on BioCoat™ Poly-D-Lysine 96 well plate with Lid (BectonDickinson and Company) and cultured at 37° C. under 5% CO₂ overnight.The medium was replaced with 100 μL/well of a Na (−) buffer (140 mMcholine chloride, 2 mM KCl, 1 mM MgCl₂, 1 mM CaCl₂, 10 mM HEPES, 5 mMTris, pH7.4) followed by incubation for 20 minutes at 37° C. under 5%CO₂. After removing the Na (−) buffer, a test compound solution whichwas prepared from Na (+) buffer (140 mM NaCl, 2 mM KCl, 1 mM MgCl₂, 1 mMCaCl₂, 10 mM HEPES, 5 mM Tris, pH7.4) containing BSA was added theretoat 40 μL/well. In addition, Na (+) buffer containing 8 kBq of ¹⁴C-AMGand 2 mM AMG was added thereto at 40 L/well, and was mixed well. Na (−)buffer containing BSA was added to a blank well at 40 μL/well andadditionally adding a Na (+) buffer containing 8 kBq of ¹⁴C-AMG and 2 mMAMG, and was mixed well. Cells were incubated for 1 hour at 37° C. under5% CO₂. After the reaction, the cells were washed twice with 100 μL/wellof iced wash buffer (100 mM AMG, 140 mM choline chloride, 2 mM KCl, 1 mMMgCl₂, 1 mM CaCl₂, 10 mM HEPES, 5 mM Tris, pH7.4), then lysed in 50μL/well of a 0.2N aqueous solution of NaOH. The cell lysate wastransferred to OptiPlate96 (Perkin-Elmer) and 100 μL/well ofMicroScint-40 (Perkin-Elmer) was dispensed. The radioactivity wascounted by TOPCOUNT NXT (Perkin-Elmer).

A data was obtained by deducting the average value (CPM) of blank wellsfrom the average value (CPM) of each treated well. The inhibition ratio(%) was calculated by the following formula: inhibition rate(%)=[(A−B)/A]×100, where A is a data of the solvent control, and B is adata of a test compound. IC50 values (50% Inhibition Concentration) of atest compound was calculated based on two concentrations which have theinhibition rate before as well as after 50% and their inhibition rates.The each result of Examples 1 to 234 and Examples 249 to 605 is shown inthe following tables 3 and 4.

TABLE 3 human Example SGLT1 % No. IC₅₀ (uM) inhibition 1 0.004 2 0.00343 0.0062 4 0.0086 5 0.0069 6 0.0072 7 0.033 8 0.02 9 1.6 10 5.5 110.0046 12 4.4 13 0.25 14 0.012 15 0.04 16 11.7 17 0.066 18 0.031 190.033 20 0.15 21 0.68 22 0.0047 23 0.0074 24 0.13 25 0.0018 26 0.0035 270.023 28 0.052 29 0.024 30 0.095 31 0.27 32 0.012 33 0.0061 34 0.0068 350.015 36 0.0094 37 0.016 38 0.13 39 0.35 40 0.65 41 1.9 42 0.19 43 0.01144 0.034 45 0.0043 46 0.0037 47 0.42 48 0.0035 49 0.012 50 0.022 51 0.0852 0.0037 53 0.0038 54 0.01 55 0.018 56 14.3 57 0.23 58 3.5 59 0.044 600.017 61 0.021 62 0.47 63 2.4 64 0.012 65 0.04 66 0.21 67  29% (0.1 uM)68 0.0067 69 0.018 70 0.0016 71 0.0035 72 0.0047 73 0.013 74 0.0031 750.0039 76 0.0017 77 0.002 78 0.0077 79 0.022 80 0.22 81  43% (0.3 uM) 820.012 83 0.011 84 0.0072 85 0.05 86 0.054 87 0.11 88 0.017 89 0.14 900.034 91 0.0018 92 0.025 93 0.031 94 0.01 95 0.0024 96 0.37 97 0.01 980.03 99 0.073 100 0.0019 101 0.0024 102 0.0022 103 0.005 104 0.0098 1050.037 106 0.0068 107 0.044 108  45% (0.1 uM) 109 0.065 110 0.085 1110.046 112 0.083 113 0.012 114 0.027 115 0.041 116 0.0061 117 0.0014 1189.3 119 0.57 120 0.0045 121 0.011 122   9% (1 uM) 123 0.005 124 0.17 1250.017 126 0.0012 127 0.0014 128 0.017 129 0.028 130 0.0013 131 0.0063132 0.0009 133 0.011 134 0.0068 135 0.011 136 0.028 137 0.014 138 0.0015139 0.0017 140 0.0011 141 0.0055 142 0.0092 143 0.0065 144 0.0013 145 43% (1 uM) 146  38% (0.1 uM) 147 0.015 148 0.01 149 0.0095 150 0.0077151 0.019 152 0.0093 153 0.0033 154 0.0011 155 0.019 156 0.0027 1570.013 158 0.0034 159 0.017 160 0.011 161 0.022 162 0.019 163 0.0071 1640.0026 165 0.022 166 0.0029 167 0.015 168 0.036 169   4% (0.1 uM) 1700.003 171 0.0083 172 0.0055 173 0.013 174   9% (1 uM) 175 40% (0.1 uM)176 0.055 177 0.056 178 0.014 179 0.019 180 −10% (0.3 uM) 181 0.0043 1820.0038 183 20.1   3% 184 (0.03 uM) 185 0.066 186 0.075 187 0.042 1880.023 189 0.2 190 0.13 191 0.054 192   6% (0.3 uM) 193 0.0013 194 0.0007195 0.0083 196 0.0048 197 0.18 198 0.067 199  40% (0.3 uM) 200 0.12 2010.093 202 0.012 203 0.0014 204 0.018 205 0.0036 206 0.0048 207 0.0047208 0.0013 209 0.0092 210 0.0059 211 0.017 212 0.0058 213 0.014 2140.0023 215 0.0014 216 0.0087 217 0.0062 218  26% (0.1 uM) 219 20% (0.1uM) 220  16% (0.1 uM) 221  15% (0.1 uM) 222 0.0041 223 0.0023 224 0.0063225 0.0039 226 0.0033 227 0.0021 228 0.0086 229 0.0031 230 0.012 2310.0067 232 0.032 233 0.02 234 0.0074

TABLE 4 Example human SGLT1 No. IC₅₀ (uM) % Inhibition 235 0.0034 2360.00535 237 0.00385 238 0.0079 239 0.007 240 0.02 241 0.00995 242 0.009243 0.014 244 0.008 245 0.019 246 0.0115 247 0.022 248 0.025 249 0.039250 0.0034 251 41% (0.1 uM) 252 7% (0.03 uM) 253 0.014 254 49% (0.3 uM)255 7% (0.3 uM) 256 3% (0.3 uM) 257 0.076 258 0.023 259 20% (0.1 uM) 2600.023 261 0.00377 262 0.006 263 0.37 264 0.039 265 17% (0.1 uM) 2660.045 267 0.081 268 0.0085 269 0.092 270 0.045 271 0.29 272 0.037 2730.027 274 0.18 275 48% (0.1 uM) 276 30% (0.1 uM) 277 48% (0.1 uM) 27834% (0.1 uM) 279 0.0175 280 0.0098 281 0.0215 282 0.0099 283 0.11 2840.075 285 0.021 286 0.03 287 0.012 288 0.0115 289 0.0045 290 0.0055 2910.0051 292 43% (0.1 uM) 293 27% (0.1 uM) 294 0.0245 295 0.029 296 48%(0.1 uM) 297 0.071 298 38% (0.1 uM) 299 0.033 300 0.038 301 0.063 3020.0015 303 0.0047 304 0.01 305 0.029 306 0.013 307 0.006 308 0.016 3090.049 310 42% (0.1 uM) 311 0.0175 312 0.022 313 0.0195 314 0.015 3150.0155 316 0.039 317 40% (0.1 uM) 318 0.0032 319 0.028 320 0.003 3210.022 322 0.0047 323 0.0048 324 0.0022 325 0.047 326 0.015 327 15% (0.3uM) 328 0.029 329 35% (0.3 uM) 330 11% (0.3 uM) 331 0.022 332 0.022 3330.02 334 0.0063 335 0.016 336 0.025 337 0.032 338 0.017 339 0.057 3400.016 341 0.06 342 0.045 343 0.0072 344 0.00335 345 0.0079 346 0.0027347 11% (0.3 uM) 348 26% (0.3 uM) 349 0.072 350 0.025 351 0.032 3520.014 353 0.016 354 0.079 355 0.0315 356 0.011 357 0.031 358 0.017 3590.039 360 0.0015 361 33% (0.1 uM) 362 0.03 363 0.013 364 0.0083 3650.018 366 0.02 367 0.0115 368 0.056 369 0.015 370 0.00635 371 0.036 3720.014 373 0.0053 374 0.0088 375 0.013 376 0.031 377 0.0097 378 0.021 3790.00525 380 0.00675 381 0.0115 382 0.012 383 0.014 384 0.048 385 0.007386 0.035 387 0.0125 388 0.00535 389 0.015 390 0.0094 391 0.00375 3920.0057 393 0.00525 394 0.015 395 0.013 396 0.031 397 0.016 398 7% (0.1uM) 399 0.019 400 0.015 401 0.013 402 0.017 403 0.012 404 0.018 405 29%(0.1 uM) 406 0.00785 407 0.0076 408 0.000 409 0.012 410 0.022 411 0.0044412 0.01095 413 48% (0.1 uM) 414 0.01145 415 0.013 416 0.015 417 0.0043418 0.00235 419 0.00475 420 0.047 421 0.02 422 0.014 423 0.016 4240.0071 425 0.00185 426 0.00205 427 49% (0.1 uM) 428 31% (0.1 uM) 429 40%(0.1 uM) 430 8% (0.1 uM) 431 21% (0.1 uM) 432 14% (0.1 uM) 433 8% (0.1uM) 434 0.021 435 0.00345 436 0.019 437 0.0045 438 0.0031 439 45% (0.1uM) 440 0.037 441 0.009 442 0.015 443 0.011 444 0.01 445 0.0067 4460.0056 447 0.0047 448 0.0043 449 0.0023 450 0.0081 451 0.0033 452 0.0017453 0.0017 454 0.002 455 0.0031 456 0.0034 457 0.0037 458 0.0059 4590.0048 460 0.0021 461 0.0014 462 0.0034 463 0.0011 464 0.0014 465 0.0017466 0.016 467 0.026 468 0.017 469 0.0052 470 0.007 471 0.015 472 0.0047473 0.0075 474 0.0073 475 0.0031 476 0.021 477 0.025 478 0.036 479 46%(0.1 uM) 480 0.0068 481 0.0087 482 0.012 483 0.059 484 0.0042 485 0.0041486 0.0065 487 0.023 488 0.018 489 0.011 490 0.0076 491 0.0065 492 0.019493 0.0082 494 0.0091 495 0.022 496 0.0069 497 0.0033 498 0.07 499 4%(0.1 uM) 500 19% (0.1 uM) 501 0.069 502 0.081 503 −17% (0.1 uM) 5040.023 505 0.011 506 0.0047 507 50% (0.1 uM) 508 0.02 509 0.038 5100.0083 511 0.0079 512 0.016 513 0.0032 514 0.004 515 0.012 516 0.0083517 0.0038 518 0.011 519 0.013 520 0.018 521 0.00515 522 0.0053 5230.00215 524 0.027 525 0.018 526 0.0092 527 0.0085 528 0.0036 529 0.0023530 40% (0.1 uM) 531 0.03 532 26% (0.1 uM) 533 0.0021 534 0.0018 5350.0028 536 15% (0.1 uM) 537 1% (0.1 uM) 538 33% (0.1 uM) 539 35% (0.1uM) 540 0.048 541 24% (0.1 uM) 542 18% (0.1 uM) 543 15% (0.1 uM) 544 21%(0.1 uM) 545 9% (0.1 uM) 546 0.0057 547 0.043 548 3% (0.1 uM) 549 41%(0.1 uM) 550 29% (0.1 uM) 551 42% (0.1 uM) 552 8% (0.1 uM) 553 31% (0.1uM) 554 32% (0.1 uM) 555 0.024 556 23% (0.1 uM) 557 48% (0.1 uM) 5580.038 559 0.0077 560 0.024 561 0.0055 562 0.013 563 57% (0.00265 uM) 5640.045 565 0.011 566 22% (0.3 uM) 567 0.014 568 27% (0.3 uM) 569 29% (0.1uM) 570 0.0087 571 0.0093 572 0.0051 573 0.013 574 0.017 575 0.012 5760.019 577 0.0067 578 0.0085 579 0.023 580 0.0076 581 0.012 582 47% (0.1uM) 583 48% (0.1 uM) 584 0.084 585 0.013 586 0.046 587 0.04 588 0.04 5890.055 590 0.013 591 0.019 592 0.015 593 0.01 594 0.066 595 0.01 5960.035 597 0.06 598 0.047 599 0.027 600 0.041 601 0.031 602 0.028 6030.016 604 N.T 605 N.T

[Formulations]

The formulation examples of the present invention include the followingformulations. However, the present invention is not intended to belimited thereto.

Formulation 1 (Preparation of Capsule)

1) Compound 1 30 mg 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg4) Magnesium stearate  1 mg

1), 2), 3) and 4) are mixed to fill in a gelatin capsule.

Formulation 2 (Preparation of Tablet)

1) Compound 1 10 g 2) Lactose 50 g 3) Cornstarch 15 g 4) Carmellosecalcium 44 g 5) Magnesium stearate  1 g

The whole amount of 1), 2) and 3) and 30 g of 4) are combined withwater, dried in vacuo, and then granulated. The resulting granules aremixed with 14 g of 4) and 1 g of 5), and pressed into tablets by atableting machine. Then, 1000 tablets wherein Compound 1 (10 mg) iscomprised in each tablet are obtained.

INDUSTRIAL APPLICABILITY

The compound or a pharmaceutically acceptable salt thereof in thepresent invention is useful for the treatment and/or prevention ofvarious diseases or conditions which are expected to be improved bycontrolling SGLT1 activity because it has SGLT1 inhibitory activity.Such diseases or conditions include, for example, diabetes such as typeII diabetes, obesity, diabetic complications (e.g., retinopathy,nephropathy and neuropathy which are known as microangiopathy, andcerebrovascular disease, ischemic heart disease and arteriosclerosisobliterans which are known as macroangiopathy), hypertrophiccardiomyopathy, ischemic heart disease, cancer and constipation.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20180346449A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A compound or a pharmaceutically acceptable salt thereof representedby the general formula [Ib]:

wherein Ring Cy is (1) C₆₋₁₀ aryl, (2) C₃₋₈ cycloalkyl or (3) C₃₋₈cycloalkenyl, n1 is 0, 1, 2, 3 or 4, R^(1a) is (1) a halogen atom, (2)hydroxy, (3) carboxy, (4) a C₁₋₆ alkyl group, (5) a C₂₋₈ alkenyl group,(6) a C₂₋₈ alkynyl group, (7) a C₁₋₆ alkoxy group, (8) a C₃₋₆ cycloalkylgroup, (9) a halo C₁₋₆ alkyl group, (10) a hydroxy C₁₋₆ alkyl group,(11) a C₁₋₆ alkoxy C₁₋₆ alkyl group, (12) a halo C₁₋₆ alkoxy C₁₋₆ alkylgroup, (13) a C₁₋₆ alkylsulfonyl C₁₋₆ alkyl group, (14) a halo C₁₋₆alkylsulfonyl C₁₋₆ alkyl group, (15) a halo C₁₋₆ alkylamino C₁₋₆ alkylgroup, (16) a C₃₋₆ cycloalkyl C₂₋₆ alkynyl group, (17) a halo C₁₋₆alkoxy group, (18) a carboxy C₁₋₆ alkoxy group, (19) a C₁₋₆alkylsulfanyl group, (20) a C₁₋₆ alkylsulfonyl group, (21) a halo C₁₋₆alkylsulfonyl group, (22) a C₁₋₈ alkylcarbonyl group, (23) a C₁₋₆alkyloxycarbonyl group, (24) a group represented by the Formula:

wherein R₅ is (a) a hydrogen atom or (b) a C₁₋₆ alkyl group, and R₆ is(a) a C₁₋₆ alkyl group or (b) a halo C₁₋₆ alkyl group, (25) a saturatedheterocyclo C₁₋₆ alkyl group (the saturated heterocycle is of 4-memberedto 6-membered saturated heterocycle having 1 to 2 heteroatoms selectedfrom nitrogen, oxygen, and sulfur) or (26) a saturated heterocyclo oxyC₁₋₆ alkyl group (the saturated heterocycle is of 4-membered to6-membered saturated heterocycle having 1 to 2 heteroatoms selected fromnitrogen, oxygen, and sulfur), provided when n1 is 2, 3 or 4, R^(1a)each is the same or different, R^(2a) is (1) a C₁₋₈ alkyl group, (2) aC₃₋₈ cycloalkyl C₁₋₆ alkyl group, (3) a C₆₋₁₀ aryl C₁₋₆ alkyl group, (4)a saturated heterocyclo C₁₋₆ alkyl group (the saturated heterocycle isof 4-membered to 6-membered saturated heterocycle having 1 to 2heteroatoms selected from nitrogen, oxygen, and sulfur), (5) a C₃₋₈cycloalkyl group, (6) a halo C₁₋₆ alkyl group, (7) a C₁₋₆ alkoxy C₁₋₆alkyl group, (8) a halo C₃₋₈ cycloalkyl group, (9) a C₆₋₁₀ aryl group(the C₆₋₁₀ aryl group is optionally substituted by 1 to 4 substituentsselected from (a) a halogen atom, (b) hydroxy, (c) a C₁₋₆ alkyl group,(d) a C₂₋₈ alkenyl group, (e) a C₂₋₆ alkynyl group, (f) a C₁₋₆ alkoxygroup, (g) a halo C₁₋₆ alkyl group, (h) a C₁₋₆ alkoxy C₁₋₆ alkyl group,(i) a halo C₁₋₆ alkoxy group, (j) a hydroxy C₁₋₆ alkoxy group, (k) aC₁₋₆ alkoxy C₁₋₆ alkoxy group, (l) a carboxy C₁₋₆ alkoxy group, (m) aC₆₋₁₀ aryl C₁₋₆ alkoxy group, (n) a C₁₋₆ alkylsulfanyl C₁₋₆ alkoxygroup, (o) a C₁₋₆ alkylsulfonyl C₁₋₆ alkoxy group, (p) a C₆₋₁₀ aryl C₁₋₆alkoxy C₁₋₆ alkoxy group, (q) a saturated heterocyclo C₁₋₆ alkoxy group(the saturated heterocycle is of 4-membered to 6-membered saturatedheterocycle having 1 to 2 heteroatoms selected from nitrogen, oxygen,and sulfur, and is optionally substituted by 1 to 2 C₁₋₆ alkyl groups),(r) a saturated heterocyclo oxy group (the saturated heterocycle is a4-membered to 6-membered saturated heterocycle having 1 to 2 heteroatomsselected from nitrogen, oxygen, and sulfur), (s) a C₃₋₈ cycloalkyloxygroup, (t) a C₁₋₆ alkoxycarbonyloxy group and (u) a C₁₋₆ alkylsulfonylgroup), or (10) a saturated heterocycle group (the saturated heterocycleis of 4-membered to 6-membered saturated heterocycle having 1 to 2heteroatoms selected from nitrogen, oxygen, and sulfur, and isoptionally substituted by 1 to 4 C₁₋₆ alkyl groups), and Ring Cy^(a) isa group selected from (1) a group represented by the Formula:

wherein m2 is 1, 2 or 3, m3 is 1, 2 or 3, n3 is 1 or 2, (2) a grouprepresented by the Formula:

wherein m4 is 0, 1, 2 or 3, m5 is 0, 1 or 2, provided sum of m4 and m5is 1 or more, (3) a group represented by the Formula:

wherein m4 is 0, 1, 2 or 3, m5 is 0, 1 or 2, provided sum of m4 and m5is 1 or more, (4) a group represented by the Formula:

wherein m6 is 0, 1 or 2, m7 is 0, 1 or 2, provided sum of m6 and m7 is 1or more, (5) a group represented by the Formula:

wherein m6 is 0, 1 or 2, m7 is 0, 1 or 2, provided sum of m6 and m7 is 1or more, (6) a group represented by the Formula:

wherein m8 is 1 or 2, m9 is 1 or 2, and (7) a group represented by theFormula:

wherein m8 is 1 or 2, m9 is 1 or 2, n2 is 0, 1, 2, 3 or 4, R^(3a) is (1)hydroxy, (2) a C₁₋₆ alkyl group or (3) a hydroxy C₁₋₆ alkyl group,provided when n2 is 2, 3 or 4, R^(3a) each is the same or different,R^(3b) is (1) hydroxy, (2) a C₁₋₆ alkyl group (which optionally form aC₃₋₆ cycloalkyl group together with the carbon to which it is attachedand the carbon adjacent thereto) or (3) a hydroxy C₁₋₆ alkyl group, or(4) when two R^(3b) are attached to the same carbon, they optionallyform a C₃₋₆ cycloalkyl group together with the carbon to which they areattached, provided, when n2 is 2, 3 or 4, each R^(3b) is the same ordifferent, and R^(4b) is (1) a hydrogen atom, (2) a C₁₋₆ alkyl group,(3) a carboxy C₁₋₆ alkyl group, (4) a halo C₁₋₆ alkyl group or (5) a C₁6 alkoxy C₁₋₆ alkyl group.
 2. The compound or a pharmaceuticallyacceptable salt thereof according to claim 1, wherein Ring Cy^(a) isselected from (1) a group represented by the Formula:

wherein m4 is 0, 1, 2 or 3, m5 is 0, 1 or 2, provided sum of m4 and m5is 1 or more, (2) a group represented by the Formula:

wherein m6 is 0, 1 or 2, m7 is 0, 1 or 2, provided sum of m6 and m7 is 1or more, (3) a group represented by the Formula:

wherein m6 is 0, 1 or 2, m7 is 0, 1 or 2, provided sum of m6 and m7 is 1or more, (4) a group represented by the Formula:

wherein m8 is 1 or 2, m9 is 1 or 2, and (5) a group represented by theFormula:

wherein m8 is 1 or 2, m9 is 1 or 2, n2 is 0, 1, 2, 3 or 4, R^(3a) is (1)hydroxy, (2) a C₁₋₆ alkyl group or (3) a hydroxy C₁₋₆ alkyl group,provided when n2 is 2, 3 or 4, each R^(3a) is the same or different,R^(3b) is (1) hydroxy, (2) a C₁₋₆ alkyl group (which optionally form aC₃₋₆ cycloalkyl group together with the carbon to which it is attachedand the carbon adjacent thereto) or (3) a hydroxy C₁₋₆ alkyl group, or(4) when two R^(3b) are attached to the same carbon, they optionallyform a C₃₋₆ cycloalkyl group together with the carbon to which they areattached, provided, when n2 is 2, 3 or 4, each R^(3b) is the same ordifferent, and R^(4b) is (1) a hydrogen atom, (2) a C₁₋₆ alkyl group,(3) a carboxy C₁₋₆ alkyl group, (4) a halo C₁₋₆ alkyl group or (5) aC₁₋₆ alkoxy C₁₋₆ alkyl group.
 3. The compound or a pharmaceuticallyacceptable salt thereof according to claim 1, wherein Ring Cy^(a) isselected from (1) a group represented by the Formula:

herein, m4 is 0, 1, 2 or 3, m5 is 0, 1 or 2, provided sum of m4 and m5is 1 or more, and (2) a group represented by the Formula:

wherein m6 is 0, 1 or 2, m7 is 0, 1 or 2, provided sum of m6 and m7 is 1or more, n2 is 0, 1, 2, 3 or 4, R^(3a) is (1) hydroxy, (2) a C₁₋₆ alkylgroup or (3) a hydroxy C₁₋₆ alkyl group, provided, when n2 is 2, 3 or 4,each R^(3a) is the same or different, R^(3b) is (1) hydroxy, (2) a C₁₋₆alkyl group (which optionally form a C₃₋₆ cycloalkyl group together withthe carbon to which it is attached and the carbon adjacent thereto) or(3) a hydroxy C₁₋₆ alkyl group, or (4) when two R^(3b) are attached tothe same carbon, they optionally form a C₃₋₆ cycloalkyl group togetherwith the carbon to which they are attached, provided, when n2 is 2, 3 or4, each R^(3b) is the same or different, and R^(4b) is (1) a hydrogenatom, (2) a C₁₋₆ alkyl group, (3) a carboxy C₁₋₆ alkyl group, (4) a haloC₁₋₆ alkyl group or (5) a C₁₋₆ alkoxy C₁₋₆ alkyl group.
 4. The compoundor a pharmaceutically acceptable salt thereof according to claim 1,wherein Ring Cy^(a) is selected from (1) a group represented by theFormula:

wherein n2 is 0, 1, 2, 3 or 4, and (2) a group represented by theFormula:

wherein n2 is 0 or 1, R^(3a) is (1) hydroxy, (2) a C₁₋₆ alkyl group or(3) a hydroxy C₁₋₆ alkyl group, and R^(3b) is (1) hydroxy, (2) a C₁₋₆alkyl group (which optionally form a C₃₋₆ cycloalkyl group together withthe carbon to which it is attached and the carbon adjacent thereto) or(3) a hydroxy C₁₋₆ alkyl group, or (4) when two R^(3b) are attached tothe same carbon, they optionally form a C₃₋₆ cycloalkyl group togetherwith the carbon to which they are attached, provided, when n2 is 2, 3 or4, each R^(3b) is the same or different, and R^(4b) is (1) a hydrogenatom, (2) a C₁₋₆ alkyl group, (3) a carboxy C₁₋₆ alkyl group, (4) a haloC₁₋₆ alkyl group or (5) a C₁₋₆ alkoxy C₁₋₆ alkyl group.
 5. The compoundor a pharmaceutically acceptable salt thereof according to any one ofclaims 1 to 4, wherein the ring Cy is C₆₋₁₀ aryl.
 6. The compound or apharmaceutically acceptable salt thereof according to claim 5, whereinthe ring Cy is phenyl.
 7. The compound or a pharmaceutically acceptablesalt thereof according to any one of claims 1 to 6 wherein R^(1a) is (1)a halogen atom, (2) a C₁₋₆ alkyl group, (3) a C₁₋₆ alkoxy group, (4) ahalo C₁₋₆ alkyl group, (5) a C₁₋₆ alkoxy C₁₋₆ alkyl group, (6) a haloC₁₋₆ alkoxy C₁₋₆ alkyl group or (7) a halo C₁₋₆ alkoxy group, providedwhen n1 is 2, 3, or 4, R^(1a) each is the same or different.
 8. Thecompound or a pharmaceutically acceptable salt thereof according to anyone of claims 1 to 7, wherein R^(2a) is a C₆₋₁₀ aryl group (the C₆₋₁₀aryl group is optionally substituted by 1 to 4 substituents selectedfrom (a) a halogen atom, (b) a C₁₋₆ alkyl group, (c) a C₁₋₆ alkoxy groupand (d) a carboxy C₁₋₆ alkoxy group).
 9. The compound or apharmaceutically acceptable salt thereof according to claim 8, whereinR^(2a) is a phenyl group (the phenyl group is optionally substituted by1 to 4 substituents selected from (a) a halogen atom, (b) a C₁₋₆ alkylgroup, (c) a C₁₋₆ alkoxy group and (d) a carboxy C₁₋₆ alkoxy group). 10.The compound or pharmaceutically acceptable salt thereof of claim 1,wherein the compound is selected from the following Formulae:


11. A pharmaceutical composition which comprises a compound or apharmaceutically acceptable salt thereof according to any one of claims1 to 10 and a pharmaceutically acceptable carrier.
 12. A SGLT1 inhibitorwhich comprises a compound or a pharmaceutically acceptable salt thereofaccording to any one of claims 1 to
 10. 13. An agent for treating orpreventing diabetes which comprises a compound or a pharmaceuticallyacceptable salt thereof according to any one of claims 1 to
 10. 14. Theagent for treating or preventing diabetes according to claim 13, whereindiabetes is type II diabetes mellitus.
 15. A method for inhibiting SGLT1which comprises administrating to mammals a therapeutically effectiveamount of a compound or a pharmaceutically acceptable salt thereofaccording to any one of claims 1 to
 10. 16. A method for treating orpreventing diabetes which comprises administrating to mammals atherapeutically effective amount of a compound or a pharmaceuticallyacceptable salt thereof according to any one of claims 1 to
 10. 17. Themethod according to claim 16, wherein the diabetes is type II diabetesmellitus.
 18. Use of a compound or a pharmaceutically acceptable saltthereof according to any one of claims 1 to 10 for manufacturing a SGLT1inhibitor.
 19. Use of a compound or a pharmaceutically acceptable saltthereof according to any one of claims 1 to 10 for manufacturing anagent for treating or preventing diabetes.
 20. The use according toclaim 19 wherein the diabetes is type II diabetes mellitus.